No retraction, correction or concern found when last checked on Oct 16, 2026.

Wnt/β-catenin signaling in cancers and targeted therapies

Fanyuan Yu, Changhao Yu, Feifei Li and 6 more

Signal Transduction and Targeted Therapy · 2021 · Review · CC BY

Abstract

Wnt/β-catenin signaling has been broadly implicated in human cancers and experimental cancer models of animals. Aberrant activation of Wnt/β-catenin signaling is tightly linked with the increment of prevalence, advancement of malignant progression, development of poor prognostics, and even ascendence of the cancer-associated mortality. Early experimental investigations have proposed the theoretical potential that efficient repression of this signaling might provide promising therapeutic choices in managing various types of cancers. Up to date, many therapies targeting Wnt/β-catenin signaling in cancers have been developed, which is assumed to endow clinicians with new opportunities of developing more satisfactory and precise remedies for cancer patients with aberrant Wnt/β-catenin signaling. However, current facts indicate that the clinical translations of Wnt/β-catenin signaling-dependent targeted therapies have faced un-neglectable crises and challenges. Therefore, in this study, we systematically reviewed the most updated knowledge of Wnt/β-catenin signaling in cancers and relatively targeted therapies to generate a clearer and more accurate awareness of both the developmental stage and underlying limitations of Wnt/β-catenin-targeted therapies in cancers. Insights of this study will help readers better understand the roles of Wnt/β-catenin signaling in cancers and provide insights to acknowledge the current opportunities and challenges of targeting this signaling in cancers.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 16, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

1As an evolutionarily conserved signaling that governs numerously vital embryonic and somatic processes, such as cell fate determination, organogenesis, tissue homeostasis, and a variety of pathological conditions, Wnt/β-catenin signaling also plays crucial roles in cancers. Aberrant Wnt/β-catenin signaling has been uncovered to be tightly woven with many aspects of cancers, including the onset, progression, malignant transformation, and so on., Evidence-based medicine has further proved that the abnormal activation of this signaling showed non-negligible effects on cancer-associated mortality.– Despite these broad acknowledgments of the significant impact of Wnt/β-catenin signaling on cancers, advances in targeted therapies remain largely incipient. Considering the extremely heavy clinical burden of Wnt/β-catenin-associated cancers globally, it is urgent to comprehensively summarize the up-to-date knowledge of Wnt/β-catenin signaling in cancers and to clarify the current status and challenges of developing Wnt/β-catenin-associated targeted therapies.

2Collectively, it is necessary to systematically review the experimental and clinical knowledge of Wnt/β-catenin signaling in cancers and present the status quo of Wnt/β-catenin-targeted therapies in cancers. With the rapid development of modern pharmacology and evidence-based medicine, certain approaches of targeting Wnt/β-catenin signaling in cancers have already achieved the path of clinical trials. These promising advances will endow researchers and clinicians with more choices and fundaments to better manage aberrant Wnt/β-catenin-associated cancers. In this article, we have systematically reviewed the most updated knowledge of Wnt/β-catenin signaling in caners and targeted therapies in accordance. Therefore, we sought to provide readers with the latest progress of Wnt/β-catenin signaling in cancers and demonstrate both opportunities and challenges of Wnt/β-catenin signaling-dependent targeted therapies in cancers.

Brief intro of Wnt/β-catenin

3The nomination of Wnt is after wingless in drosophila and int1 in mammalians., As the prerequisite of understanding the roles of Wnt/β-catenin in cancer, in this part, we will briefly introduce the signaling transduction. Numerous researches have already depicted an integral scene of the core components of β-catenin-dependent Wnt signaling. It consists of extracellular ligands, agonists; trans-membraned receptors/co-receptors; intracellular compounds including disheveled (Dsh in drosophila and Dvl in mammals), degradation complex comprising glycogen synthase kinase 3 β (Gsk3β), casein kinase1α (CK1α), Axin/conductin, and adenomatous polyposis coli (Apc), β-catenin, and transcription factors.

4Extracellular Wnt ligands are inevitable to switch-on downstream signaling cascade. The extracellular secretion and functions of Wnt ligands depend on post-transcriptional modifications. The post-transcriptional modifications of Wnt ligands mainly include glycosylation, palmitoylation, and acylation.– Especially, the acylation is necessary for extracellular transport and receptor/co-receptors recognition and bounding.,

5With respect to the receptor/co-receptors of Wnt/β-catenin signaling, including frizzled (Fzd) receptors and Lrp co-receptors. For Fzds family, it owns at least 10 members of G protein-coupled receptor (GPCR). The highly conserved cysteine-rich domain (CRD) of Fzds manipulates the ligand recognition and binding., In addition, as co-receptors to Wnt ligands, Lrps consist of Lrp5 and 6, whose extracellular domains interact with Fzds and then its intracellular domains trigger further signaling transduction., In addition to receptor/co-receptors, there also exist certain extracellular regulators that can influence the ligand–receptor/co-receptors interaction. For instance, the R-spondins (Rspo), member 1/2/3/4, which coordinates with leucine-rich repeat-containing GPCR (Lgr) 4/5/6 to enhance Wnt/β-catenin signaling.– Specifically, the Rspo-Lgr complex increases Lrp5/6 phosphorylation and inactivates Wnt repressors Rnf43 and Znrf3.,, Rnf43 and Znrf3 are E3 ubiquitin ligases that mediate the degradation of Fzds., Furthermore, certain intracellular regulators can also abolish the signaling cascade downstream of ligand–receptor interaction. Dsh, a cytoplasmic protein with three highly conserved sections, directly interacts with the C-terminal of Fzds via its PDZ region.,

6Finally, after receiving the upstream activation signals, β-catenin functions as the ultimate effector., Without canonical Wnt ligands, β-catenin binds to cadherin of cytoplasmic sides rather than being transported into the nucleus, further phosphorylated and eliminated by degradation complex.– Phosphorylated β-catenin is degraded by the ubiquitin-proteasome system to keep the low level of free β-catenin in the cytoplasm., Conversely, once being activated, intracellular β-catenin is rapidly enriched, and then trans-localized into the nucleus to regulate gene expressions., Apart from directly manipulating gene transcription as a TF, β-catenin can also form a transcriptional complex with Lef/Tcf via its armadillo repeats regions., Intriguingly, the degradation complex of β-catenin is concise and complicated. As soon as the degradation complex converts into the active form, it phosphorylates β-catenin for ubiquitination, which sends it to the proteasome. When the degradation complex is deactivated, β-catenin accumulates and influxes into the nucleus to initiate the transcription of downstream genes.

Wnt/β-catenin signaling in cancers

7Basing on the subtle summary of Wnt/β-catenin signaling, in this part, we aimed to further demonstrate the roles of Wnt/β-catenin signaling in cancers. Specifically, we will follow the progressively organized structure going behind the signal conduction cascade of this pathway: extracellular, membrane-linked, and intracellular (cytoplasmatic and nuclear) compositions.

Porcupine (Porc)

8Porc is a membrane-bound O-acyltransferase (MBOAT), by whose palmitoylation function Wnt ligands can be subsequently secreted and recognized. After being palmitoylated, Wnt ligands will bind to wntless and be transported into cell membrane from Golgi apparatus (Fig. 1). Thereout repressing Porc is a candidate way against tumors with aberrant Wnt/β-catenin activation. Nowadays, inhibitors targeting Porc have been uncovered to be underlyingly beneficial for diverse types of cancers.

Ligands

9The Fzds are responsible for recognizing and receiving canonical Wnt ligands, which are defined as β-catenin-dependent ligands. In this review, we focus on the canonical Wnt ligands, including Wnt1, 2, 3, and 3a.

Wnt1

10Previous studies have shown that knockout of wg, the homolog gene of mammalian Wnt1, caused the wingless phenotype in Drosophila., Experimental and clinical analysis further revealed the frequent abnormal upregulations of Wnt1 in massive cancers.– Abnormal Wnt1 expressing patients comprised the majority of cancer patients of non-small cell lung cancer (NSCLC). Nevertheless, a Wnt1-dependent gene, Wnt1-inducible signaling pathway protein 2 (WISP2), was reported to effectively undermine the immunologic evasion of cancer cells., In addition to the direct involvements of Wnt1 in cancers, certain upstream modulators of Wnt1 can repress the viability of a few sorts of cancer cells, containing RU484, MicroRNA-140-5p, and SJ26.–

11Encouragingly, inhibiting Wnt1 relieved the growth and progression of breast cancer in a transgenic murine model. Conversely, overexpression of Wnt1 promoted the growth of cancers., Therapeutically, Blocking Wnt1 has been found to strengthen the apoptosis of colorectal cancer (CRC) cells via the utilization of Wif1, Wnt1-specific siRNAs, and neutralizing antibodies.

Wnt2

12Similarly, the overexpression of Wnt2 has also been detected in human fibroadenomas, breast cancer, pancreatic cancer, and CRC.– Despite the concerns that in CRC (CRC) Wnt2 perhaps accelerated its migration and invasion,, on the contrary, in other kinds of cancers such as gastric, pancreatic, and NSCLC, Wnt2 aggregates the cancer progression.– With respect to its therapeutic potentials, direct silence of Wnt2 alleviated the xenograft breast cancer growth and rescued the malignance and the chemo-drugs resistance in breast cancers.,

Wnt3

13Wnt3 is a homologous gene of Wnt3a, and the similarity is up to 84.2% total amino-acid identity in humans. The level of Wnt3 mRNA was obviously upregulated in primary breast and rectal cancer. Wnt3 plays a cacoethic role in multiple cancers, such as CRC, breast cancer,, NSCLC,, and prostate cancer. Specifically, the excitation of Wnt3 speeds up the tumorigenesis of CRC. Furthermore, it has been implied to elevate the epithelium–mesenchyme transit (EMT) of breast cancers through Wnt/β-catenin., In terms of therapeutic choices, the downregulation relieved the progression of CRC by reducing cancer cell proliferation and migration. For NSCLC, knockdown of Wnt3 could increase drug sensitivity., In prostate cancer, inhibiting Wnt3 signaling by the deficiency of trophinin-associated protein attenuated the cancer growth. The demethylation of non-coding RNA miR-1247-5p provided an optional remedy for human hepatocellular carcinoma (HCC) via inhibiting Wnt3.

Wnt3a

14As the strongest Wnt/β-catenin stimulator, Wnt3a has been proposed to participate in numerous cancers. For instance, in most solid tumors, Wnt3a promoted the tumorigenesis and progression of CRC, prostate, liver, and lung cancers.– Mechanistically, Wnt3a enhanced cancer cells proliferation, differentiation, migration, and self-renewal,– and conversely inhibits cell apoptosis depending on activating Wnt/β-catenin. In leukemia, a study indicated that Wnt3a, activating Wnt/β-catenin, suppressed the proliferation of cancer cells.

15Therapeutically, in prostate cancers, targeting Wnt3a through Traf6 either Tmem64 restrained tumor development., For liver cancers, targeting Wnt3a by miRNA-195 and miRNA‑214 presented the possibility of cancer management.,

Fzds

16Fzds, a subset of seven-transmembrane protein, are the principal receptors of canonical Wnt ligands. Fzds, mainly including subfamilies Fzd1/2/7, Fzd3/6, Fzd4, Fzd5/8, and Fzd9/10, are ubiquitously expressed in most animal species but not in plants and single-cell eukaryotes. The N-terminal CRD domain of Fzds spontaneously binds to Wnt ligands and Lrp5/6 co-receptors., The C-terminus of Fzds is localized in the cytosol which recruits and binds to Dsh to intracellularly trigger subsequent signal cascades. Fzds and Lrp5/6 are indispensable for Wnt/β-catenin activation, and non-eligibly, Fzds receptors, and Lrp5/6 co-receptors are both oncogenic under certain conditions.– Except for main canonical Wnt ligands compromising Wnt1, 3, and 3a, there still exists several non-canonical Wnt ligands including Wnt5a, 7a, and 7b known to interact with Fzds under specialized circumstances.–

17Fzd3 could be promotive for the development of Ewing sarcoma and breast cancer.– Also, Fzd4 and Fzd5 were reported to be significantly increased in prostate cancer., Fzd6 highly emerged in CRC, breast cancer, and bladder cancer.– Most importantly, Fzd7 is vitally essential in numerous cancers like HCC, breast cancer, gastric cancer, CRC and so on. Detailedly, Wnt3a-Fzd7 dependent Wnt/β-catenin signaling exaggerated the tumorigenesis and advancement of HCC. Prostate cancer metastasis is related to ERG-induced Fzd8 up-regulation. Besides, Fzd10 plays an important positive role in various cancers, at least in CRC development, but the level of Fzd10 is down in metastatic cancers. The Fzd10 expression may be a prognostic marker in CRC, and the same is true in synovial sarcoma.

18Next, the following part is about to concisely summarize the potential therapeutic values of targeting Fzds in cancers. Fzd1 is related to drug resistance in cancers, subsequently, inhibiting Fzd1 attenuating the resistance.– Moreover, repressing Fzd1 via knocking down Fzd1, using rosiglitazone or miR-135b decreased the metastasis of breast cancer.– For targeting Fzd3, by which some non-coding RNAs, like miRNA-505, miRNA-493, and HOXD cluster antisense RNA 1 relieve cancer progression.– And Fzd7 deficiency is enough to combat Apc carcinogenesising. Fzd3 has a certain promotion function on Ewing sarcoma, breast cancer.– Research shows that Fzd4 expression is extremely high in human prostate cancer cells and some non-coding RNA, like microRNA-505, microRNA-493, and HOXD cluster antisense RNA 1 (HOXD-AS1), relieves cancer progression by Fzd3.,– Fzd5 functions in prostate and gastric cancer,, and Fzd6 in colorectal, breast, and bladder cancer.– Fzd7 overexpression is detected in numerous cancers, like hepatocellular, breast, and CRC. WNT3A-Fzd7 interaction activates Wnt/β-catenin signaling in human hepatocellular carcinoma cells and promotes tumorigenesis. Fzd7 is vitally essential for the development of gastric cancer and it is the major receptor of Wnt ligands. Inhibitor targeting Fzd7 is effective for treating gastric cancer, no matter with Apc mutations or not. Fzd7 may be an extraordinarily effective therapy for gastric and CRCs., ERG is overexpression in most prostate cancer and Wnt/β-catenin signaling is activated. Prostate cancer metastasis is related to ERG inducing Fzd8 up-regulation. Besides, Fzd10 plays an important positive role in various cancers, at least in CRC development, but the level of Fzd10 is down in metastatic cancers. The Fzd10 expression may be a prognostic marker in CRC, and the same is true in synovial sarcoma.

Lrps

19As co-receptors of Wnt ligands Lrp5/6 are tightly associated with the growth of Wnt-hypersensitive tumors. The single-domain antibody fragments of Lrp5/6 can effectively relieve the development of intestinal cancers. Generally, the truncated LRP5 amplified Wnt/β-catenin signaling to severely promote the growth of parathyroid tumors. Herein, stabilizing of Lrp5 by Hsp90ab1 enhanced gastric cancer progression. Moreover, LRP6 also plays a positive role in various cancers, such as CRC, breast cancer, prostate cancer, and so on.,– Basing on these facts, LRP6 neutralizing antibodies were demonstrated to repress tumorigenesis. It is of note that contrarily targeting Lrp5/6 may be not eligible for managing metastasis of breast cancer.

The abolishers of receptor/co-receptors

20Znrf3 and Rnf43, as transmembrane E3 ubiquitin ligases on cell surface, are negative regulators of Wnt/β-catenin signaling., Researches indicated that Znrf3/Rnf43 attenuated Wnt signaling by selectively ubiquitinating receptors/co-receptors of Wnts (Fzds and Lrps) to advance proteins degradation., Rspos, binding with Lgrs, can activate Wnt/β-catenin signaling by dually enhancing Lrp5/6 activity and removing Znrf3/Rnf43 from cell membrane, (Fig. 2). Rspos could as well activate Wnt/β-catenin signaling via interacting with HSPGs independent of Lgrs. Interestingly, Rspo2 mutations were unraveled to associate with tetra-amelia syndrome, contributing to the destruction of Rspo2-Lgr binding. Current evidence depicted the crucial roles of somatic mutations of Rspos in cancers. In detail, Rspo fusions are regarded as important for tumorigenesis in CRC, by activating Wnt/β-catenin signaling. Rspo2/3 chromosome rearrangements can initiate and maintain tumor development absolutely through Wnt signals.

21Apart from Rspos, the mutations of Znrf3/Rnf43 were also proposed to participate in CRC. The most common mutations of Znrf3/Rnf43 were missense and truncating mutations, respectively. Znrf3 mutations were frequently detected in adrenocortical carcinoma, uterine corpus endometrial carcinoma, and skin cutaneous melanoma. Similarly, Rnf43 mutations were overall found in uterine corpus endometrial carcinoma, stomach adenocarcinoma, colorectal adenocarcinoma, ovarian cancer, and pancreatic ductal adenocarcinoma., Znrf3 and Rnf43 were not essential in the intestine but dysregulation of Znrf3/Rnf43 was important for the growth of CRC.,, Mutations of Rnf43, resulting in E3 ubiquitin ligases function loss, promoted CRC development and poor prognosis. Inactivating mutations of Rnf43 were related to Wnt dependency. LGK974, targeting on Wnt/β-catenin signaling, alleviated Rnf43 mutation-associated pancreatic cancer cell proliferation, however, which did not affect the non-mutant cancers. For CRC, Rspo/Rnf43 dysregulation plays a positive role in development and dominates over Znrf3., There still needs further researches to explore the relation between Wnt/β-catenin and Znrf3/Rnf43, as well as them in cancers.

The antagonists of receptor/co-receptors

22Endogenous repressors of Wnt/β-catenin signaling can be divided into two groups: the reversible and the irreversible ones. The former group including competitively binds to the receptor/co-receptor to block the ligand–receptors interaction, like Dkks, Sost, sfrp, and so on. The latter group functions through different mechanisms. Notum deacetylates Wnts and permanently invalidates the recognition. Tikis hydrolyze Wnts to polymerize ligands and finally abolish ligand function. Considering that there are bare therapeutic analyses of targeting these irreversible repressors in cancer until now, in this part we will not further discuss relative aspects. (for more details, please find in Table 1)

Adenomatous polyposis coli (Apc)

23Apc gene locates on chromosome 5q21-q22, containing 8535 amino acids and encoding a cytoplasmic protein around 310 kDa. More than 1500 mutations of Apc were detected over multiple tumors, and majorly in CRC. Meanwhile, the most mutant sites were located on exon 15. Over 700 somatic mutations of Apc resulted in various types of cancers by truncating Apc protein that was dependent on nonsense (34%) or frameshift mutation (62%)., Mutations of Apc can cause familial adenomatous polyposis (FAP), which is also the major hereditary carcinogenic factor in CRC progression., A study showed that around 72% of Apc mutations were detected spreading throughout the Apc gene in early-onset CRC.

24Apc gene has been identified as a vital suppressor in CRC genesis by inactivating Wnt/β-catenin signaling and stabilizing chromosomes. And mutations of Apc directly or indirectly lead to tumorigenesis as well. Mechanistically, Apc regulates β-catenin phosphorylation and restrains the nuclear trans-localization of β-catenin, (Fig. 3). The three-hit hypothesis suggests that the abnormal mutation of Apc results in β-catenin abundance and abnormal activation of Wnt/β-catenin signaling in CRC. In contrast, the abnormal expression or truncation of Apc weakened the ability of tumor inhibition. Studies indicated that R2 and B motifs of Apc were the binding sites of Apc-Gsk3β/Axin, by which complex the diversity and structural stability of Axin were promoted. The loss-of-function (LoF) of Apc may be an essential contributor to various cancers, especially CRC. At present, experimental rodent models of CRC were initiated by knocking out of Apc.–

25Apc also suppresses other cancers, such as lung, breast, gastric, and prostate cancers, excepting for CRC.– The DNA methylation of Apc promoter is closely associated with various cancers, like lung cancer and prostatic cancer., The methylation reduces the normal expression of Apc in cancers, resulting in abnormal activation of the Wnt/β-catenin signaling pathway. Overall, this evidence indicated the repressive role of Apc in cancers, thus making it a promising way to remedy cancers via enhancing Apc function or restore the normal function of Apc.

Axin

26Axin proteins, including Axin1 and Axin2, maintain β-catenin phosphorylation, thereby inhibiting signaling pathways by assembling the degradation complex with Gsk3β, Apc, and Ck1 (Fig. 3). Intriguingly, even though the Apc has been blocked, therapies targeting Axin could still be effective., Axin was identified as a suppressor in various cancers through majorly inhibiting Wnt/β-catenin signaling. Axins consist of three functional domains, the RGS domain of amino-terminal, the DIX domain of carboxyl-terminal, and the central region (AxinCR). Separately, the RGS domain is responsible for interacting with Apc to phosphorylate β-catenin. The DIX domain directly affects Dsh protein,, and AxinCR binds to β-catenin and Gsk3β to regulate Wnt/β-catenin signaling.,,

27Some researches indicated that a single point mutation of Axin destroyed the stabilization of the RGS domain, resulting in Axin polymerization. The function of the Apc complex is affected by Axin self-polymerization. Inhibition of Axin and Apc complex together promoted tumor genesis and progression by enhancing Wnt/β-catenin signaling., Controlling Axin polymerization may be a potential therapeutic choice to suppress cancer development., Mutations of AxinCR were reported to accelerate the tumorigenesis in the following cancers: HCC, colorectal adenomas, ovarian carcinomas, lung carcinomas, and sporadic medulloblastomas. Therefore, erasing or eliminating the mutations of Axin could a promising method to combat diverse cancers.

Axin1/2 mutation in cancers

28Axin1 mutations were detected widely in HCC., This mutation could phenocopy various tumors in animal models., Axin2 can partially compensate for the functional impairment caused by Axin1 mutation.,, Axin2 dysfunction was associated with a variety of tumors, including endometrial cancer, CRC,– lung cancer,, and breast cancer.– In these cancers, Axin2 performed suppressive roles by mainly constraining the level of β-catenin.

Tankyrase (Tnks) in cancers

29Tankyrase, consisting of two members (Tnks1 and Tnks2 in most species), participates in modulating Wnt/β-catenin signaling. Tankyrase1/2 is a poly (ADP-ribose) polymerase (PARP), attaching PAR chains onto substrates by its catalytic action., The enzymes bind and then PARylate Axins, utterly, the Axins are ubiquitylated and degraded., Additionally, researches showed that tankyrase enhanced Wnt/β-catenin signaling., A series of studies further proved that tankyrase could suppress cancer development via inhibiting the Wnt/β-catenin signaling pathway.,–

Glycogen synthase kinase 3 (Gsk-3)

30In Wnt/β-catenin signaling, generally, Gsk3 controls β-catenin degradation by comprising a degradation complex.,, Axin, phosphorylated by Gsk3, binds to and phosphorylates β-catenin, resulting in β-catenin degradation by ubiquitin proteasome.,, It is interesting that Gsk3 and CK1α can phosphorylate Wnt-co-receptor LRP6 to play positive roles in Wnt/β-catenin signaling activation.– The dissociated Gsk3 from the degradation complex is essential for the nuclear shuttle of β-catenin– (Fig. 3). So far, targeting Gsk3 may be a potential therapy for cancers. In certain cancers, Gsk3 may crosstalk with several pathways, including PI3K/PTEN/AKT/Gsk-3/mTORC1 and NF-κB pathway, and the details will be discussed in blow.– Despite the function of Gsk3β is relatively clear in HCC, targeting Gsk3β in cancers still needs far more researches to elucidate its concise effects.

CK1

31First encountered for phosphorylating casein in vitro, the CK1s are serine/threonine kinases that serve as pathway signal transductor in most eukaryotic cells. They are ubiquitously expressed in human tissues all through the developmental and adult period, and the Wnt/β-catenin signaling pathway is just one of the pathways that CK1s impact. The mechanisms of CK1 isoforms on regulating Wnt/β-catenin pathway are complicated. Depending on the substrates and subcellular location, CK1s play distinguished roles. To begin with, CK1α is the typical isoform for down-regulates Wnt/β-catenin signaling. As a composition of the degradation complex, CK1α initiates the phosphorylation of β-catenin. In fact, CK1δ/ε are also involved in this process by phosphorylating Apc (which strengthens the affinity of Apc to β-catenin), in collaboration with Gsk3., Furthermore, CK1ε phosphorylates and activities Dvl; however, this action also provokes negative feedback to inhibit Wnt/β-catenin pathway (vide infra). In terms of activation, on receiving Wnt ligands, firstly CK1ε phosphorylates Dvl, then CK1γ phosphorylates the cytoplasmatic domain of Lrp6, finally recruiting CK1α and Axin to bind with Lrp6 in the signalosomes, thus delivering the signal to downstream. Other mobilization effect includes the phosphorylation of CK1ε and CK1α to Tcf3 and Pygo, respectively.,

Dvl

32The Dvls family is the transportation hub of Wnt/β-catenin signaling pathway. To adapt to this responsibility, the three highly evolutionally conserved domains of Dvls are the binding sites of various proteins. DIX, a highly conserved domain, is indispensable for the recognition of Axin. Moreover, DIX mediated the polymerization of Dvl monomer, which assembles as the anchoring site for Axin and Gsk3β. This process may have significant effects on the ligand–receptor/co-receptor internalization. CK1ε phosphorylating mediated DIX-E3 ligase interaction ubiquitinates Dvl, abolishing the polymerization of Dvls, ultimately inhibiting Wnt/β-catenin signaling. Next, the PDZ domain lying in the central part of Dvls, essential for the signal conduct from Fzd to downstream molecules, is also the most druggable region in Dvl. CK1 also targets this site. Near the C-terminal region is the DEP domain, whose role is still obscure in the canonical Wnt signaling pathway. Despite these three classic domains, Dvls also have a basic region and a proline-rich region, which may have effects in protein–protein interactions (PPI). Newish founds also indicated that Dvls shuttled between the membrane and the nucleus, and chances were that two distinct Dvls pools may exist., However, these discoveries were vague about the druggability of Dvl. So in this review, we suspended this topic aside.

β-catenin and Lef/Tcf in cancers

33β-catenin is a multifunctional protein, which is versatile in various cellular events and human diseases. The very core of Wnt/β-catenin is the balance between the phosphorylation/dephosphorylation and degradation of β-catenin. In brief, the destruction complex phosphorylates β-catenin and to degradeβ-catenin by ubiquitin-proteasome system. There are some other kinases are associated with protein phosphorylation, including PP1, PP2A, and PP2C in Wnt/β-catenin signaling pathway. PP1 and PP2C play a positive role in Wnt/β-catenin signaling by dephosphorylating Axin., PP2A, a principal Ser/Thr phosphatase, involves multiple proteins phosphorylation, and importantly, the kinase malfunction could result in several cancers.– PR55α, as a regulatory subunit of PP2A, can enhance the activity of Wnt/β-catenin signaling by regulating PP2A to suppress β-catenin phosphorylation. Hsp105, a PP2A regulator, is overexpressed in various tumors to reduce β-catenin degradation. Researches showed that PP2A dephosphorylated β-catenin to increase β-catenin accumulation.– Therefore, it may be an alternative way to target PP2A in aberrant Wnt/β-catenin signaling cancers.

34The stabilization of β-catenin is heavily associated with various cancers. In detail, the mutations of β-catenin are of great significance in tumorigenesis, progression, and prognosis of cancers., In blow, we will detailedly discuss the mutations of β-catenin in cancers. The constitutive activation form of β-catenin, the exon 3 mutations, is believed to regulate the genesis of hereditary non-polyposis CRC. In CRC, there are several mutations of β-catenin, leading to abnormally activated Wnt/β-catenin signaling. The mutations of β-catenin are commonly detected in HCC, uterine corpus endometrial carcinoma, adrenocortical carcinoma, and so on.– The mutations of β-catenin majorly are missense that block Gsk3β consensus sites to activate Wnt/β-catenin signaling., Besides, β-catenin mutations may be a significant carcinogenic factor in endometrial carcinoma., Apart from the direct regulatory functions on tumorigenesis, the characteristics of β-catenin can also provide an approach to estimate the stage of low-graded, early-staged endometrial cancer recurrence.,

35In addition to the direct transcription regulation of β-catenin as a transcription factor (TF), it can also form diverse types of transcription complex. β-catenin–Lef/Tcf includes Tcf/Lef, p300/CBP, and other proteins to assist β-catenin in binding to specific DNA sequence– (Fig. 3). Tcf binds to Groucho/TLE, CtBP, and histone deacetylase proteins when β-catenin signaling is not activated.– Tcf/Lef separates from Groucho/TLE and then composites β-catenin–Lef/Tcf complex, depending on X-linked inhibitor of apoptosis (XIAP) monoubiquitylating Groucho (Gro)/TLE. CBP promotes the transactivation of β-catenin/Tcf cooperating with thymine DNA glycosylase. In addition, the transcription complex recruits p300/CBP,, Bcl9, Pontin522, Reptin52, Brg-1,, Mllt/Af10-Dot1, SOX10, p68/p72, βTrCp1/Fbw1a, FOXM1–, and yes-associated protein 1 (YAP1).,

36However, in CRC, HIFα can competitively bound to β-catenin to abolish the Tcf4/β-catenin complex, then enhancing the hypoxia tolerance of cancer cells to increase the survival in an anoxic environment. Interestingly, HIF2α binds to the β-catenin–Tcf complex at a different site from HIF1α to recruit p300 and then enhances Wnt/β-catenin signaling. The synergistic actions of HIF2α and β-catenin increase the proliferation of renal cell carcinoma cells. Accordingly, utilizing Tanshinone IIA can inhibit CRC angiogenesis by means of interrupting HIF-1α/β-catenin/Tcf3/Lef1 signaling.,

37Besides, HOXB13, SOX4, RUNX3, CDK8, TCTP, and Daxx participate in regulating Wnt/β-catenin signaling to target Tcf in numerous cancers. Specifically, HOXB13 expression was downregulated in colorectal and prostate cancer., And it inhibited the growth of cancers by reducing Tcf and c-myc protein levels., RUNX3 inhibited Wnt/β-catenin signaling by comprising of a ternary complex with β-catenin–Tcf and attenuates growth and progression of multiple cancers, especially in gastric cancer., SOX4 can increase β-catenin–Lef/Tcf transcriptional activity through upregulating Tcf4., CDK8, an oncogene in CRC, partly functions by co-activating β-catenin–Tcf complex. Thus, CDK8 may be a promising target for β-catenin-associated cancers. The translationally controlled tumor protein (TCTP) can enhance the transcription complex activity by increasing the ability of β-catenin–Tcf binding and then inducing the growth of glioma tumor. In summary, HOXB13 and RUNX3 are identified as suppressors of Wnt/β-catenin signaling by obstructing Tcf4 activity to inhibit tumorigenesis and cancer progression.,

Tnik

38Traf2- and Nck-interacting kinase (Tnik) is one member of germinal center kinases (GCKs) that can activate the c-Jun N-terminal kinase pathway. Tnik is an essential component for Wnt/β-catenin signaling to maintain physiological cell homeostasis., Tnik can directly interact with β-catenin and Tcf to modulate Wnt/β-catenin signaling, (Fig. 3). Therapeutically, Tnik is a crucial target for the treatment of CRC. In CRC cells, Tnik activates the transcriptional capability of Tcf4 through phosphorylation., It has been shown that the growth of CRC cells was strictly dependent on Tnik stimulation. Indeed, after knocking down Tnik, the growth of xenograft CRC cells was brought to stall. And patients with overexpression of Tnik were manifested with poor postsurgical outcomes. Over 80% of CRCs have mutations in Apc, which makes the only molecule downstream of Apc a therapeutic target.

Wnt/β-catenin and Notch signaling

39Notch signaling widely interacts with Wnt/β-catenin signaling in cell homeostasis and embryo development. Notch signaling also involves in the wingless development with Wnt/β-catenin signaling., Notch can directly inhibit Armadillo/β-catenin to enhance destruction complex activity., Besides, LNX2, a regulator of Notch, enhances the cell vitality in Wnt/β-catenin-associated CRC. In turn, β-catenin–Lef/Tcf can reciprocally activate Notch signaling by inducing the expression of Jagged1 and Dll1, which are the ligands of Notch signaling., In addition, β-catenin reduces Notch1 ubiquitination and increases the expression of Hes1 to interfere with Notch signaling transduction., The synergistic action of Wnt/β-catenin and Notch signalings promotes tumorigenesis and cancer progression. Apparently, the potential remedies of inhibiting this synergistic function can be beneficial in cancer therapies.–

Wnt/β-catenin and Sonic hedgehog (Shh) signaling

40The Sonic hedgehog signaling is another important interactor of β-catenin-dependent Wnt signaling., Smo, a receptor of Shh ligands, once being triggered via Shh, can activate Gli activities.– Glis, including Gli1-3, are the ultimate effectors of Shh signaling as transcriptional regulators. Intriguingly, Gsk3β and CK1α can both phosphorylate and active Glis to reciprocally enhance Wnt/β-catenin signaling activity., The crosstalk of Shh-Wnt/β-catenin involves the relapse, invasion, and metastasis of certain cancers, so that the repression of this crosstalk may alleviate the progression, migration, and invasion of cancers. For instance, cyclopamine, as an inhibitor of Shh signaling, postpones the invasion of CRC by suppressing β-catenin–Tcf transcriptional activity.

Categories of pharmacology

41Drugs targeting canonical Wnt signaling can be divided into two major subtypes, which are small-molecule inhibitor (SMI) and monoclonal antibody (mAb). SMIs usually refer to chemically synthesized compounds with a molecular weight of less than 1 kDa. In recent years, taking advantage of the in-depth learning of molecular and biological mechanisms in cancers, targeted drugs with fewer side effects plus better specificity than traditional chemo drugs have been developed. Theirs strengthens include but are not limited to (1) pronounced permeability into tissues and cells owing to the small-molecule weight; (2) larger volume of distribution; (3) diversified methods of drug delivery; (4) generally better oral tolerance and oral bioavailability after chemical modification. In contrast, mAbs cannot be taken orally, and are often administered by injection, which results in poor patient compliance. Even being directly injected, the distribution of mAbs in vivo is relatively limited. They cannot often easily reach therapeutic concentrations in some specialized tissues (such as the brain) as SMIs do. And as the inherent antigenicity of mAbs, they are likely to cause immune responses. mAbs are generally dominantly distributed in the kidneys, followed by the liver and spleen. In addition, they appear with non-linear pharmacokinetic characteristics, longer half-life, and smaller volume of distribution. Though mAbs can only act on extracellular targets, they have still achieved remarkable antitumor performances in comparison to SMIs, which is attributing to their different pharmacological mechanisms.

42SMIs can bind to receptors with stronger affinity than the original ligands. On some occasions, they modify the structures of the receptors so that the ligands cannot be recognized. Moreover, certain SMIs may act as ATP analogs and bind to kinase sites in the cytoplasm, making the receptors unrecognizable.

43The advantage of mAbs is not only to directly act on the extracellular and membrane-linked targets but also to activate the intrinsic internal immune system to indirectly exert antitumor effects. With respect to the direct functions, mAbs bind to receptors or ligands to block signal recognition or mediate internalization to reduce the density of receptors on the cell membrane surface. When acting indirectly, mAbs induce complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), or complement-dependent cell-mediated cytotoxicity (CDCC)., Therefore, in in vivo experiments with a complete immune system, mAbs may show better antitumor effects than in in vitro experiments. In addition, mAbs can serve as the vehicle to achieve precision medicine, such as targeting radiogen to tumors.

44To sum up, in practical scenarios, mAbs are more competent for the treatment of hematological tumors than solid tumors as a consequence of their antigenicity and large particles. SMIs can target proteins even in the nucleus and penetrate the blood-brain barrier easily, thus preferentially suitable for treating solid tumors. Even if being humanized, mAbs are inevitable to arouse unintended immune reactions. Meanwhile, SMIs have poor antigenicity, but low specificity, which also brings a higher risk of side effects. Briefly, SMIs and mAbs exhibit diverse characteristics and various indications of cancers.

45In addition to SMIs and mAbs, an under-developed category of Wnt/β-catenin-targeted therapy goes to peptides and peptide-associated modified drugs. Peptides have been put into use as drugs long ago, but obvious limitations delayed their clinical advancements. Peptidomimetic, a kind of peptide-associated modified drug, is much smaller than the parental molecule, yet having low antigenicity, good oral bioavailability, good permeability, and better diffusing to the target. Different from SMIs, their half-life is generally very short and has very rapid excretion. Although this feature reduces the risk of side effects, it contrarily causes difficulties to reach satisfactory concentration.

SMIs targeting Porc

46Porc inhibitors are well-acknowledged to block Wnt signaling with a low risk of off-target. Moreover, it was revealed that the exhaustion of canonical Wnt ligands prevented cancer cell proliferation but induced differentiation. Therefore, inhibiting Porc may be a mild therapy that could prevent tumor growth rather than directly causing lethal effects. It has been previously described that Znrf3/Rnf43 are important negative regulators of Wnt signaling. The LoF mutation of Znrf3/Rnf43 was reported to be oncogenic, and Porc inhibitors had shown a remarkable potency in this aspect.,, Unfortunately, the absence of Apc is likely to induce a Wnt ligand-independent signaling, so tumors with Apc LoF mutations may be resistant to Porc inhibitors. And Picco et al. reported that in a CRC cell line (VACO6) with RSPO3 fusion, long-term exposure (3 months) of a Porc inhibitor (LGK974) with incremental doses can induce drug resistance. This kind of drug resistance is accomplished by LoF of Axin1 in the VACO6.

47Contemporarily, there are a growing number of reports showing the side effects of Porc inhibitors, among which bone loss is the most frequent outcome., Two studies indicated that LGK974, WNT-C5, or ETC159 can lead to bone loss by diminished osteogenesis and increased osteolysis. These bone loss phenotypes were reported to even appear under the condition of effective dosages of Porc inhibitors.– Hopefully, this side effect can be relieved by co-administrating diphosphonate (alendronate, zoledronic acid for instance). And other adverse effects may be solved by lower doses through the incorporation of other antitumor drugs.

LGK974

48Also known as WNT974, LGK974 is a potent SMI targeting Porc. A preclinical study showed the effective performance of LGK974 among variable neoplasm models with good oral tolerance. Even this study systematically examined many organs such as the intestine, stomach, and skin, but unfortunately giving an ignorance to bone tissue. Besides, it was discovered that all human head and neck squamous cell carcinoma (HNSCC) cell lines with Notch nonsense mutation were more sensitive to LGK974. Inspired by this, a team signed up for a clinical trial attempting to use LGK974 to treat HNSCC patients with Notch LoF mutation (Table 2). But this project was abandoned as found retrieval. Another study showed the incredible use of LGK974 in Rnf43 nonsense mutation cell lines in pancreatic ductal adenocarcinoma (PDAC). Both of the two clinical studies illustrated a delayed effect of proliferation inhibition by LGK974. Specifically, after a single administration, there still remains some β-catenin in the cytoplasm to initiate the downstream transcriptional activities. LGK974 also preliminarily demonstrated a reliable tumor-suppressive effect in vitro on neuroendocrine tumor and ovarian cancer.,

49A study using uncovered similar impairment of bone mass in two different doses of LGK974 in mice (3 and 6 mg/kg/d for 7 days). Another study expanded the dose range (from 1to 30 mg/kg/d) and showed an all ranges covered bone loss after continuous treatment for 4 weeks. What’s worrying is that the dosage of 3 mg/kg/d for mice is necessary to reach a significant tumor repression. And the exposure to a high dose of LGK974 (20 mg/kg/d) results in prominent intestinal toxicity. Fortunately, as the sustaining treatment of LKG974 is not required for tumor treatment, the practical clinical dosage may not bring so many side effects. Notably, the clinical dosage of LGK974 is still in exploration without explicit results posted.,

ETC159

50ETC159, originally named ETC-1922159, is a potent orally available SMI for Porc. Madan et al. identified its high efficiency in CRC with Rspo translocations. This study also inspected intestinal tissues, but still neglected bones. ETC159 can perform effectively synergistic effects with PI3k/mTor inhibitor GDC-0941 in PDAC with Rnf43 LoF mutation. Based on the outstanding behavior of ETC159 in a preclinical experiment, another phase II clinical trial targeting advanced solid tumors has been carried out. Interestingly, part B of this trial evaluates the combination usage of ETC159 and pembrolizumab. But no results have been posted up to date (Tabl. 2).

51Bone loss has been observed after 4 weeks of administration in a dosage of 3–30 mg/kg/d. The research team adjusts administration frequency from qd to qod to validate the hypothesis of whether the bone loss could be attenuated after a full metabolic cycle of ETC159. Results showed that there were no significant differences in several estimated outcomes of bone between treated daily and treated every other day. By the way, ETC131, a similar compound of ETC159, is only used for in vitro assays as a result of its inferior oral bioavailability.

CGX1321

52CGX1321 is a novel Porc inhibitor, yet only a few studies have researched into this small molecule. For experimental analysis, it has been discovered for a good performance in CRC with fused Rspo. Further in-depth studies respectively included the combined usage of CGX1321 and immune checkpoint blockade therapy to treat ovarian cancer (but the results were unsatisfactory), and liposome encapsulation as a vehicle to deliver CGX1321 to treat cancer stem cells (with expected results).

53As for the clinical trial of CGX1321, it was solely used in solid tumors including gastrointestinal tumors (Table 2). And the combination of CGX1321 with pembrolizumab in CRCs was constructed to evaluate the safety. Yet no results have been posted currently.

WNT-C59

54This drug is not well-studied when compared with LGK974 or ETC159, but it exclusively targets mammalian Porc. It owns good oral tolerance and efficacy in the MMTV-Wnt1 mouse mammary cancer model, the Znrf3/Rnf43−/− mouse CRC model. And WNT-C59 satisfactorily prevented tumor growth in mice xenografted with SUNE1 or HNE1 (two nasopharyngeal carcinoma cell lines). In addition, WNT-C59 can reverse the resistance of trichostatin A in human pancreatic cells. However, when administrated at 10 mg/kg/d for 7 or 21 days, bone loss was observed in mice. This should be taken into consideration as the potential side effect of WNT-C59 in cancer therapies.

GNF-1331/GNF-6231

55GNF-1331 is a precursor drug, and the optimization of it brings on the discoveries of LGK974 and GNF-6231. Currently, GNF-6231 is still a brand-new molecule without clinical studies. But it worked well in MMTV-Wnt1 patient-derived xenograft (PDX) mice model, by reducing Axin2 expression.

IWP

56Relying on the screening approach of the phenotype of inhibition of Wnt production, this kind of molecule was named as “inhibitors of Wnt production (IWP)”. In this study, the research group then verified the exclusive activity of inhibiting Wnt-related Porc function by using IWPs. IWP has three family members, IWP-1, −2, and -L6, all of which oppress Wnt/β-catenin signaling by competing for the active sites of Porc with Wntless. IWP-2 and IWP-L6 had poor metabolic stability in mice, but at least IWP-L6 showed relatively better stability in human. IWPs may synergist with PRI-724 to induce apoptosis in HNSCC through inhibition of both Porc and CBP/β-catenin. However, as IWPs have a similar structure to certain CK1 inhibitors, much research have proposed the effects on CK1 isoform suppression of IWPs., IWP-2 and IWP-4 inhibited the proliferation of various cancer cells via antagonizing Porc and CK1α. The growth of gastric cancer cells was restrained via the IWPs-mediated downregulation of Wnt/β-catenin signaling. A similar situation occurred in HNSCC cells as well.

mAbs targeting Wnt receptors and co-receptors

57mAbs are remarkably targeted drugs especially for blocking extracellular or membrane-linked proteins. They are characterized by high affinity and low off-target accidents but have longer plasma half-life and lessened clearance rate.

OMP-18R5/OMP-54F28

58Also known as vanticumab, OMP-18R5 is a monoclonal antibody that targets human Fzd1, 2, 5, 7, and 8. And it was reported to inhibit the growth of gastric adenomas in mice models, either with or without Apc LoF mutation. OMP-54F28, namely ipafricept, is the chimera of truncated Fzd8 and IgG1 Fc region. Ipafricept shares many features with vanticumab. A study has proved the high antitumor effect of ipafricept in MMTV-Wnt1 cancer models. Moreover, the synergistic utilization of ipafricept gemcitabine demonstrated inhibitory function in a pancreatic PDX model, and significantly reduced the cancer stem cells (CSC) frequency. This combined strategy showed superior capabilities of tumor arrest over the sole usage of ipafricept either or gemcitabine.

59Encouragingly, either vanticumab or ipafricept exhibited impressive synergistic therapeutic effects with taxanes (paclitaxel, docetaxel, and cabazitaxel). Fischer et al. discovered that there existed a population of taxane-resistant cancer cells after using paclitaxel. And the successional administration of ipafricept/vanticumab prior to paclitaxel can overcome the drug-resistant effect via a sole administration of paclitaxel. Mechanically, this combined usage of ipafricept/vanticumab and paclitaxel strengthened the mitotic catastrophe.

60The adverse effects of OMPs are similar to Porc inhibitors, but OMPs showed worse impairment of bone mass. As for ipafricept, in a clinical trial in patients with advanced solid tumors, fragility fractures were reported in two participants at 20 mg/kg q3w. Another trial recruited patients inflicted with recurrent ovarian cancer, in which a patient experienced a pelvic fracture at 5 mg/kg q3w. Studies pointed out that vanticumab had a more severe side effect on bone than ipafricept. In detail, in a clinical trial with metastatic pancreatic cancer, two participants experienced fragility fractures at 7 mg/kg q2w. Additionally, in a trial attempted to treat advanced or metastatic HER2- breast cancer, vanticumab led to fragility fractures in 3 patients, including three Grade 2 events and one Grade 3 events of fracture ranking, at the regimen of 7, 14 mg/kg q2w and 8 mg/kg q4w. Surprisingly, this unintended outcome appeared under the critical supervision of bone metabolism outcomes and bone anabolic remedy of diphosphonate treatment. At last, a total of 6 patients experienced fragility fractures, leading to the abolishment of this trial. All those fracture events mentioned above were not reported as dose-limited toxicity, because they took place after the 1st 28d-window-phase. Whereas, still no studies could reach the maximum administered dose (MAD) in consideration of bone safety. Overall, though preclinical experiments exhibited a good performance of OMPs, these trials revealed a crisis of applying ipafricept/vanticumab in clinical (Table 2).

OMP-131R10

61Also named as rosmantuzumab, OMP-131R10 is a humanized mAb targeting Rspo3. Some malignant hematopoiesis cancers have aberrant Wnt/β-catenin signaling independent to Wnt ligands, due to the redundancy of Rspos in triggering Wnt/β-catenin signaling. Based on this, Salik et al. demonstrated that rosmantuzumab can impair the self-renewal and differentiation of acute myeloid leukemia cells in the PDX model, meanwhile free from influencing normal hematopoietic stem cells. For the clinical trial, a phase 1a/b trial about rosmantuzumab in advanced solid tumors and previously treated metastatic CRC is still going on (Table 2).

F2.A

62F2.A is a newly developed antibody that targets 6 of the 10 human Fzds (Fzd1/2/4/5/7/8). The developer synthesized this compound by firstly identification of anti-Fzd antibodies (F2) with a specific profile matching to OMP-18R5 and secondly using combinatorial antibody engineering to find a variant F2.A with specificity to bounding Fzd4. According to their study, F2.A could selectively bound to Fzd4 without competition with Norrin. Moreover, F2.A had a much better potency when treating Rnf43 mutated PDAC when compared to OMP-18R5 and OMP-54F28.

DKN-01

63DKN-01 is a humanized IgG4 mAb that can bound and block the activity of Dkk1. Physiologically, Wnt/β-catenin signaling activates the transcription of Dkk1, which in turn bounds LRP5/6 and block the recognition of Wnt ligands, forming a negative feedback loop. However, some tumors featured with overwhelmed Wnt/β-catenin signaling are insensitive to Dkk1. In contrast, the superfluous Dkk1 can promote tumor cell proliferation. Though the specific mechanisms are unknown, it was hypothesized that Dkk1 helped tumors escape from immune supervision. Indeed, it was reported that an intact immune system was needed for DKN-01 function in a murine model. Most clinical trials are researching on DKN-01, most of which focused on the digestive system such as the gastroesophageal, intestine, liver, and biliary tract cancers, and the rest focused on NSCLC, gynecologic malignancies, and multiple myeloma. DKN-01 showed satisfactory tolerance in all clinical trials. Intriguingly, some trials reported a better effect of DKN-01 in Dkk1-overexpressed patients (Table 2).

UC-961

64UC-961, also called cirmtuzumab, is a first-in-class mAb that targets ROR1. ROR1 is often highly expressed in chronic leukemia lymphoma (CLL) cells. As normal B lymphocytes do not express ROR1, UC-961 has precise and good effects in treating CLL.

OTSA-101

65Fzd10 was found ubiquitously upregulated in synovial sarcoma (SS), but scarcely detectable in normal tissues except the placenta. A group of radioimmunoconjugate humanized antibody OTSA-101 was designed to target Fzd10, whose derivations include 211At-OTSA-101, 111In-OTSA-101, and 90Y-OTSA-101. Among them, 111In-OTSA-101 is routinely used as a diagnostic tool. Whereas OTSA-101 only showed a weak antagonistic activity on the growth of SS cells. Afterall, OTSA-101 merely became a putative carrier for targeted SS radiotherapy. In preclinical experiments, a large number of cell death occurred in the PDX murine model on the first day after injection of 211At-OTSA-101. All mice in this interventional group survived, and the tumor volume was greatly diminished. However, 211At-OTSA-101 was easily accumulated in the stomach and its uptake rate of tumor cells was not as good as 111In-OTSA-101. But the inhibitory effect of 211At-OTSA-101 was much better than 90Y-OTSA-101281. Furthermore, 90Y-OTSA-101 showed obvious bone marrow suppression and significant hematotoxicity.

Foxy-5

66Sponsored and developed by WntResearch (https://www.wntresearch.com), foxy-5 is a mimic of WNT5A. Preclinical studies showed that a low level of WNT5A was correlated with a more metastatic or advanced outcome in breast and prostate cancer. In accordance, foxy-5 could prevent metastasis to some extent., At present, WntResearch has supported five clinical trials registered on NIH and EUCTR, yet with no results posted (Table 2).

CWP232291

67CWP232291, abbreviated as CWP291, can decline the transcriptional effect of canonical Wnt signaling. CWP291 was reported to suppress the growth of castration-resistant prostate cancer through the degradation of β-catenin via apoptosis-induced ER stress. In fact, CWP232204 is the active form of CWP291 in serum. Currently, CWP291 was put forward in clinical trials of treating acute myeloid leukemia (AML) and refractory myeloma without results updated (Table 2).

Tnks inhibitors

68Tankyrase is a poly-ADP polymerase (PARP), which can make Axin1/2 poly-ADP ribosylation, leading to the ubiquitination and degradation of the latter. Therefore, the silence of Tnks will result in the inhibition of the Wnt/β-catenin signaling. According to the binding sites, Tnks inhibitors can be divided into two categories: targeted nicotinamide subsites and adenosine subsites. The nicotinamide domain is ubiquitous in the PARP enzymes, and its specific site inhibitor is XAV939. For the adenosine domain, it is unique to Tnks, and many Tnks inhibitors (G007-LK, NVP-Tnks656, JW55/74, and IWR) target this site.

69Having been developed for a long time, Tnks inhibitors have shown outstanding tumor-suppressive effects in preclinical experiments, but none of them have entered into clinical trials. Of note, they were reported to possibly cause bone loss. Inhibition of Tnks (using either XAV939, IWR-1, or G007-LK) in murine models led to the accumulation of a substrate, SH3 domain-binding protein 2 (SH3BP2), which subsequently enhanced the Rankl-mediated osteoclast formation., In the human genome, the gain of function (GoF) of SH3BP2 promoted osteoclastogenesis so which led to bone loss. Although SH3BP2 can also promote the differentiation and maturation of osteoblasts, Tnks inhibitors dominantly showed an osteoclastogenesis effect in vivo, because the concentration needed for stimulating osteoblast is about 10 times higher than that of osteoclasts. Not only Tnks, but the family of PARP plays an important role in bone homeostasis. Though theoretically, pan-PARP inhibitors are presumed to have a greater influence on bone, there is currently no convincing evidence to prove their regulations of bone mass.

70In addition, Tanaka et al. found that CRC cells (whether established cell lines or patient-derived cells) with Apc-truncated mutations responded well to Tnks inhibitors (XAV939, IWR-1, and G007-LK), especially the mutations with all the 20-amino-acid repeats (the β-catenin binding sites of Apc) obliterated. Conversely, the longer Apc mutation may lead to resistance to Tnks inhibitors. These results suggested an underlying therapeutic value of Tnks for dealing with truncated Apc mutant cancers.

71XAV939 was identified as an inhibitory factor of Wnt/β-catenin signaling, originally in CRC cell lines. This SMI stabilized Axin to increase β-catenin degradation by suppressing Tnks1/2. It has been investigated that beside from CRC, XAV939 can constrain certain cancers by inhibiting the Wnt/β-catenin signaling. The combined utilization of low-dose paclitaxel and XAV939 inhibited breast cancer metastasis and the growth of triple-negative breast cancer. This mechanism was contributed to inhibiting Wnt/β-catenin signaling to enhance cancer cell apoptosis and attenuate EMT and angiogenesis. In gastric cancer, XAV939 can inhibit the invasion and metastasis of cancer cells. XAV939 and RNAi-Tnks1 inhibited the stemness and migration of cancer stem cells and accelerated cell apoptosis in neuroblastoma by attenuating the abnormal status of Wnt/β-catenin signaling., XAV939 and IWR, the inhibitors of Tnks, repressed the growth of lung cancer and reduced tumorigenesis. Experimental data proved the inhibitory effect of XAV939 and IWR on cancer cell growth in murine lung cancer models. XAV939 enhanced the ability of CD4+ lymphocytes in biochemically recurrent prostate cancer cell lines, LNCaP and PC-3.

72JW67 and JW74, two compounds as inhibitory molecules of Wnt/β-catenin signaling, can inhibit the growth of CRC by Axin2 accumulation and β-catenin degradation. JW74 and JW55 are Tnks inhibitors that bind to the lower part of donor NAD+ cleft, instead of mimicking nicotinamide. JW55 also worked well in the murine PDX CRC model with Apc mutation. G007-LK is an analog of JW74, and G244-LM is analogous to XAV939., Compound G007-LK and G244-LM can damage the proliferation, colony formation, and growth of CRC cells via activating Axins to suppress Wnt/β-catenin signaling. As an adjuvant, G007-LK can also enhance the sensitivity of glioma stem cells to a chemo drug temozolomide and CRC cells to PI3K/EGFR inhibitors.,

73As mentioned above, IWR compounds were defined based on their anti-Wnt pathway activities in a phenotypic screening assay. IWRs, including five molecules, target Wnt-dependent cancers by enhancing Axin capability to suppress Wnt/β-catenin signaling., The inhibition of IWRs has been identified in various cancers like osteosarcoma, colorectal, breast, lung, and hepatocellular cancers.,,– IWR-1 served as a good adjuvant that reversed the resistance of osteosarcoma to doxorubicin, and in vivo inhibited the growth of subcutaneous PDX osteosarcoma. Moreover, IWR-1 could inhibit the EMT of CRC by inhibiting Wnt/β-catenin transduction.

74In the following part, we are going to discuss several agents, NVP-TNKS656, AZ1366, RK-287107, and HLY78, that are Tnks inhibitors with very limited preclinical reports. For instance, NVP-TNKS656 increased the sensitivity of CRC cells to PI3K/AKT inhibitor in vivo, but the increment effect could be reversed by high FOXO3A. And NVP-TNKS656 also inhibited the metastatic and invasive EMT hallmarks of hepatoma carcinoma cells. AZ1366 is a novel inhibitor of Tnks to constrain NSCLC growth. EGFR-driven NSCLC was suppressed by the synergistic function of AZ1366 and EGFR inhibitors. AZ1366 could erase the insensitivity of CRC cells to irinotecan, and it coordinated with EGFR inhibitor to control the growth of Wnt-responsive lung cancers in the murine models. RK-287107 was claimed to inhibit Tnks1/2 four or eight times more than G007-LK. It could down-regulate the Wnt/β-catenin signaling in Apc-truncated CRC cells, but had little effects in wild-type cancer cells. An SMI from the synthetic chemical library of lycorine derivatives, 4-ethyl-5-methyl-5,6-dihydro-[1,3]dioxolo[4,5-j]phenanthridine (HLY78), activated Wnt/β-catenin signaling by targeting the DIX domain of Axin and enhanced the effect of Axin-Lrp5/6.

CK1 inhibitors

75The family of CK1 proteins has several isoforms, of which CK1α/δ/ε are involved in the canonical Wnt signaling, but their roles are distinguished. CK1α serves as a component of the destructive complex and phosphorylates β-catenin. Instead, CK1δ/ε phosphorylates Dvl leading to the stabilization of β-catenin. And CK1δ and CK1ε are also moonlighting proteins that control the circadian clock. IC261 is a selective, ATP-competitive CK1 inhibitor that has shown its high efficiency in handling CRC and glioblastoma cells., Not only that, IC261 has alternatively biological effects that may lead to the death of cancer cells independent of inhibiting the canonical Wnt pathway., In an in vitro study, IC261 induced centrosome fragmentation during mitosis independent of CK1δ. Other CK1 inhibitors include PF670 and PF480 that do not kill cancer cells.

76Also known as umbralisib, TGR-1202 is a dual kinase inhibitor that targets both PI3Kδ and CK1ε. The non-canonical Wnt pathway has been demonstrated to play an important role in CLL with CK1δ/ε overexpression. TGR-1202 is exclusively used in hematological malignancies and is currently recruited in clinical trials for treating CLL, Hodgkin’s lymphoma, mantle cell lymphoma, and so on (Table 2).

77Pyrvinium, known as an antiparasitic drug, has been approved by FDA as an orphan drug for FAP because of its exclusive CK1α agitation capability. Earlier experiments have shown that pyrvinium inhibited the proliferation of HCT116 and SW480 cell lines by selectively activating CK1α and inhibiting canonical Wnt signaling. This activation may be achieved by allosteric regulation, thereby improving the catalytic ability of CK1 without affecting the binding of substrates. Although pyrvinium also showed inhibitory ability in other Wnt/β-catenin signaling-driven tumor cell lines (SUM-149/SUM-159, and A2278), its bioavailability was low in tissues other than the intestine. In addition, pyrvinium also stimulated CK1γ, leading to Wnt signaling suppression. However, some scholars indicated pyrvinium pamoate lacked the efficacy on CK1, instead, it downregulated AKT by an undiscovered mechanism to activate Gsk3β.

Gsk3 inhibitors

78Ambiguously serving as carcinogenic or cancer suppressor, Gsk3 lies downstream of diverse signaling pathways, including the Wnt/β-catenin signaling pathway. Therefore, targeting Gsk3 has very restricted specificity to produce unexpected off-targets. Thus, this review will not thoroughly discuss Gsk3 inhibitors due to their low specificity of Wnt/β-catenin signaling. Therefore, here only lists a typical Gsk3 inhibitor that has shown good performance in inhibiting Wnt/β-catenin signaling.

79LY2090314 is a potent Gsk3α/β inhibitor that has demonstrated good cooperation with platinum agents in vitro in the treatment of melanoma, AR-V7+ prostate cancer, and neuroblastoma. But in a phase I clinical trial, the combination of LY2090314 and pemetrexed/carboplatin showed eleven DLTs in ten enrolled patients (Table 2). Other Gsk3 inhibitors like ABC1183 and CHIR-99021 are currently under exploring.

Dvl inhibitors

80Though serving as a critical conductor in the canonical Wnt pathway, only few drugs and studies targeting Dvl are available. Till now, targeting Dvl has already shown a notable potentiality for tumor treatment. For instance, Dvl2 was overexpressed in HCC and reported to link with poor prognosis. In comparison to normal adult bronchial/alveolar epithelial and peripheral blood mononuclear cells, Dvl1-3 were found to be exclusively expressed in NSCLC and CLL cells, respectively., Most drugs targeting Dvls currently are developed to selectively inhibit PDZ-Fzd interaction. Such as FJ9, it was significantly reported to cause apoptosis in melanoma and NSCLC cell lines. 3289-8625, another Dvl inhibitor, suppressed the growth of PC-3 cells. Taken together, the druggability of Dvls remains largely unknown. Urgent studies are demanded to unearth more applicable chances for drugs targeting Dvls in the future.

Agents targeting protein–protein interaction (PPI) in the nucleus

81Nuclear localization of β-catenin will initiate downstream gene expressions. This process involves the formation of a key transcription complex, β-catenin–Lef/Tcf. β-catenin-dependent transcriptional regulation is also modulated by the phosphorylation protein Tnik, and various transcription co-factors like CBP, BCL9, CREB, BRG1, etc. These proteins listed above are all potential therapeutic targets of Wnt/β-catenin signaling. Despite the most core position of β-catenin in canonical Wnt signaling, pityingly, among all previously screened SMIs, few can directly bind to β-catenin. This is because, unlike most enzymes or receptors with identifiable binding pockets, the PPI surface of β-catenin is relatively large and flat for small molecules. And the Tcf-binding domain within β-catenin is overlapped with many other proteins, making it difficult to specifically interfere with Tcf/Lef (Fig. 4). Moreover, among the limited SMIs (CWP232228 for example) that can directly bind to β-catenin, there lacks evidence of Wnt signaling inhibitory in vivo. In contrast, targeting Tnik showed more stable inhibition of canonical Wnt signaling.

Tnik inhibitors

82As mentioned above, Tnik is a critical therapeutic target of CRC. Among the Tnik inhibitors, the most commonly used are aminothiazole-based. Masuda et al. discovered a series of SMIs called NCB, classified as ATP-competitive inhibitors. After a high-throughput screening of the small-molecule compound library, they firstly found NCB-0001 (with a moderate inhibitory effect on canonical Wnt signaling in HEK293 cells), which led to the discovery of N5355 following the structural optimization. N5355 significantly reduced the expression of Wnt/β-catenin-dependent genes, such as Axin2 and cMYC, in HCT-116 cell line. What’s worth noting, N5355 did not affect the vitality of canonical Wnt signaling independent cell lines, HELA and HEL299. This research group subsequently discovered NCB-0005 (or called KY-05009), which markedly inhibited the activation of Wnt/β-catenin signaling mediated by TGF-β1 in A549 cells. Also, the NCB-0005 cooperated with the RTK inhibitor dovitinib to impede the growth of multiple myeloma cells. Their latest discovery was NCB-0846, which inhibited the growth in a variety of patient-derived CRC xenografted tumors, and abrogated the EMT of DLD-1, HCT-116, and A549 cell lines.,

83As ATP-competitive inhibitors, NCB series drugs may also have inhibitory effects on other kinases. Therefore, it should be concerned that the clinical effects of NCB drugs may not be limited to target canonical Wnt signaling. In addition to CRC, inhibitory effects of NCB drugs have also been reported in other tumors.,

Inhibitors targeting β-catenin–-Lef/Tcf complex

84Such inhibitors block the PPI between β-catenin and Tcf/Lef. However, the Tcf/Lef recognition domain on β-catenin highly overlaps with that of Axin, Apc, E-cadherin, and other proteins, which may bring potential adverse effects derived from off-targets of canonical Wnt signaling.

85In this part, we will mainly discuss the β-catenin–Lef/Tcf complex inhibitors as following: CWP232228, LF3, BC2059, PKF115-584, PKF222-815, and CGP049090. CWP232228 is such an inhibitor, which was reported to induce apoptosis and cell cycle arrest in HCT116 cells, also to show effects on liver and breast CSCs., LF3, a 4-thioureido-benzenesulfonamide derivative, reduced tumor growth and induced differentiation in a CRC xenograft murine model. Moreover, BC2059, an anthraquinone oxime-analog repressing Lef1/Tcf4 activity, was elucidated to induce the apoptosis of HL-60, HEL, and K562 significantly., BC2059 is currently testified in a phase I clinical trial of desmoid tumor (Table 2). Other drugs of β-catenin–Lef/Tcf complex inhibitors, including three fungal derivatives, PKF115-584, PKF222-815, and CGP049090, have shown prominent inhibitory effects towards CLL/AML (PKF115-584 and CGP049090) and HCC (all three agents) cells, through inducing apoptosis.– Still, some β-catenin–Tcf/Lef inhibitors need more preclinical experiments to verify their practicabilities, such as PNU74654 and 2,4-diamino-quinazoline derivatives.

Transcription co-factor inhibitors

86For less superposition and narrower PPI surface in the recognition domain, inhibitors targeting the terminal domains (unstructured or intrinsically disordered protein regions) are putative to be more specific and druggable. These regions involve the binding of transcriptional co-factors like BCL9/B9C and CBP. Indeed, the SMI 40-fluoro-N-phenyl-[1,10-biphenyl]−3-carboxamide and its derivatives showed a much greater affinity toward β-catenin/BCL9 over β-catenin/E-cadherin.

87For targeting CBP, PRI-724, and ICG-001, a pair of enantiomers, are potent inhibitors of canonical Wnt signaling that antagonize the binding of β-catenin to CBP but not affecting the viability of p300 meanwhile. They have similar effects and sometimes can be used interchangeably. Their preclinical efficiency has been demonstrated in a variable of cancer cells such as HNSCC, hepatoma carcinoma, and neuroendocrine tumor cells. A clinical trial of cancer research is still engaging but without results posted (Table 2, two of the three trials were terminated). However, they seemed to be more applicable in antifibrosis than in antitumor.,

88BCL9 provides an excellent opportunity for targeting Wnt signaling therapy. In normal cells, BCL9 expression is almost undetectable, but it reigns a set of EMT-regulated Wnt target genes in cancer cells. And after knocking out Bcl9 and B9l in mice, no obvious harmful phenotypes were found, indicating that these genes are of little importance for mammals to balance Wnt signaling in normal tissues. Based on this, Takada et al. developed the stapled peptide stabilized α helix of BCL9 (SAH-BCL9), which can snatch β-catenin from the endogenous Bcl9/Tcf/β-catenin complex with greater affinity. SAH-BCL9 showed a significant antitumor effect in both colo320 in vitro and intraperitoneally injected murine model in vivo.

Other drugs may target Wnt/β-catenin signaling

89Apart from the synthetic compounds, in recent years more and more natural products have been revealed to impact on repressing Wnt/β-catenin signaling.– The most studied may be resveratrol, a phytoalexin produced when plants are inflicted with injuries or pathogenic attacks. Resveratrol has been enrolled into two phase I clinical trials, investigating its value in the dietary supplement in CRC prophylaxis., Moreover, silibinin, an extract from the milk thistle seeds, also showed its potentiality in preventing tumorigenesis in a preclinical model.,

90In addition to natural products, many FDA-approved drugs have expanded their indications to crosstalk with Wnt/β-catenin signaling. Just as mentioned above, as an antiparasitic agent pyrvinium also inhibited Wnt/β-catenin pathway via activating CK1α, or Gsk3β., Other old drugs like niclosamide to inhibit canonical Wnt signaling by promoting Fzd1 endocytosis, celecoxib to induce the degradation of Tcf7, and salinomycin to target LRP6. Due to the functions of these old drugs for targeting Wnt/β-catenin signaling are still limitedly known, we will not continue to discuss these drugs. For more details, please find in Table 3.

Challenges of Wnt/β-catenin-targeted therapies

91Even though drug development in the field of Wnt targeted therapies in cancers has been so prosperous, no exclusive drug has yet been approved by the FDA. This dilemma has aroused an un-neglectable crisis for moving forward the targeted therapies of canonical Wnt signaling in cancers. There are still many challenges before they could be put into large-scale clinical trials. This review crudely divided these drugs into three categories: SMIs, mAbs, and modified peptides. The molecular and structural properties determine the potential diversity of the clinical applications of these three categories. mAbs and peptidomimetics are more suitable for the targets on cell membrane surface, accordingly, SMIs are more suitable for targeting Wnt receptors and intracytoplasmic kinases, and stapled peptides are suitable for disrupting PPI in the nucleus.

92For SMI, they are known for their good permeability and oral bioavailability, but off-target effects are common. This is especially inevitable for ATP-competitive drugs. mAbs are known for their unparalleled specificity, but their oral availability is poor. The mAbs have a slow clearance rate and a long half-life, which increases the burden on the liver and kidneys of the patient and increases the side effects. Besides, mAbs also have poor permeability and cannot target intracellular sites. Most importantly, current modifications of mAbs failed to decrease the antigenicity and increase tolerance. For modified peptides, they can achieve good permeability and tolerability, but a larger dose is required for them to maintain the therapeutic concentration.

93Considering the ubiquitous and extensive involvements of Wnt/β-catenin signaling in regulating various normal tissue functions, it is ineluctable to accept the unintended byproducts of targeting canonical Wnt signaling. Although it provides an ideal approach to target nuclear β-catenin in aberrant canonical Wnt signaling-associated cancers, it is currently unprocurable to develop such kinds of targeted agents because of the very limited druggability. This crisis of developing the targeted therapies of Wnt/β-catenin signaling in cancers may possibly be overcome via the in-depth analysis of the preexisting molecules. Also, more development strategies such as immunotherapy, the synergistic medications of drugs, the decrement of mAbs weight, and so on could endow us with underlying breakthroughs to realize the canonical Wnt signaling targeted therapies in cancers.

Conclusion and discussion

94Identified decades ago, Wnt/β-catenin signaling immediately generated substantial interest in the field of cancer research because of their extensive involvements and intensive roles in regulating numerous aspects of cancers, including the initiation, development, progression, diagnosis. In this study, we revealed that the status quo investigations have depicted an un-neglectable crisis of the Wnt/β-catenin-dependent targeted therapies in cancers. In detail, most of the medications targeting Wnt/β-catenin signaling in cancers have not been enrolled into clinical trials, and even the registered clinical trials remain in the very early phases of which most have not demonstrated satisfactory outcomes (Fig. 5). However, this dilemma clashed with the early evidence in in vitro and in vivo with the optimal performance of targeting Wnt/β-catenin signaling in cancers. The reasons for these poor therapeutic benefits rely on the fact that the current remedies of Wnt/β-catenin signaling-associated targeted therapies in cancers often lack satisfactory efficacy, specificity, and safety. For instance, due to the crucial roles of Wnt/β-catenin signaling in bone, many targeted therapies demonstrated obvious side effects of severe bone loss. Furthermore, certain SMIs and mAbs targeting Wnt/β-catenin signaling showed limited specificity because of the difficulty of identifying the druggable structures and sites of Wnt/β-catenin signaling components. These facts suggest that Wnt/β-catenin signaling targeted therapies in cancers are still lagging behind for a solid clinical translation.

95Nevertheless, as massive early experimental investigations have already proven the benefits of targeting Wnt/β-catenin signaling in cancers it is still worthy to further analyze the capabilities of developing Wnt/β-catenin signaling targeted therapies in the future (Fig. 6). It should be noticed that future studies are called to solve the current crisis via decreasing the side effects but improving the specificity and safety of Wnt/β-catenin signaling targeted therapies in cancers. To sum up, our review systematically exhibited the strengths and weaknesses of the most updated targeted therapies of Wnt/β-catenin signaling in cancers, aiming to generate a thorough awareness of current challenges and crises. Ultimately, this study sought to provide future studies with the issues and insights that should be taken into account for developing better-targeted therapies of Wnt/β-catenin signaling in cancers.

References 495

1.
Clevers H. Wnt/beta-catenin signaling in development and disease. Cell. 2006;127:469-480.
Not in our library10.1016/j.cell.2006.10.018
2.
Clevers H, Nusse R. Wnt/β-catenin signaling and disease. Cell. 2012;149:1192-1205.
Not in our library10.1016/j.cell.2012.05.012
3.
Le PN, et al. Wnt signaling dynamics in head and neck squamous cell cancer tumor-stroma interactions. Mol. Carcinog. 2019;58:398-410.
Not in our library10.1002/mc.22937
4.
Stewart DJ. Wnt signaling pathway in non-small cell lung cancer. J. Natl Cancer Inst. 2014;106:djt356.
Not in our library10.1093/jnci/djt356
5.
Wnt/β-Catenin Signaling in Liver Cancers · 2019
No notice
6.
Bahrami A, et al. Therapeutic potential of targeting Wnt/β-catenin pathway in treatment of colorectal cancer: rational and progress. J. Cell. Biochem. 2017;118:1979-1983.
Not in our library10.1002/jcb.25903
7.
Nusse R, Varmus HE. Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell. 1982;31:99-109.
Not in our library10.1016/0092-8674(82)90409-3
8.
Rijsewijk F, et al. The Drosophila homolog of the mouse mammary oncogene int-1 is identical to the segment polarity gene wingless. Cell. 1987;50:649-657.
Not in our library10.1016/0092-8674(87)90038-9
9.
Nusse R, Clevers H. Wnt/β-catenin signaling, disease, and emerging therapeutic modalities. Cell. 2017;169:985-999.
Not in our library10.1016/j.cell.2017.05.016
10.
Brennan KR, Brown AMC. Wnt proteins in mammary development and cancer. J. Mammary Gland Biol. Neoplasia. 2004;9:119-131.
Not in our library10.1023/b:jomg.0000037157.94207.33
11.
Kurayoshi M, Yamamoto H, Izumi S, Kikuchi A. Post-translational palmitoylation and glycosylation of Wnt-5a are necessary for its signalling. Biochem. J. 2007;402:515-523.
Not in our library10.1042/bj20061476
12.
Komekado H, Yamamoto H, Chiba T, Kikuchi A. Glycosylation and palmitoylation of Wnt-3a are coupled to produce an active form of Wnt-3a. Genes Cells Devoted Mol. Cell. Mech. 2007;12:521-534.
Not in our library10.1111/j.1365-2443.2007.01068.x
13.
Takada R, et al. Monounsaturated fatty acid modification of Wnt protein: its role in Wnt secretion. Dev. Cell. 2006;11:791-801.
Not in our library10.1016/j.devcel.2006.10.003
14.
Torres VI, Godoy JA, Inestrosa NC. Modulating Wnt signaling at the root: porcupine and Wnt acylation. Pharmacol. Ther. 2019;198:34-45.
Not in our library10.1016/j.pharmthera.2019.02.009
15.
Janda CY, Waghray D, Levin AM, Thomas C, Garcia KC. Structural basis of Wnt recognition by Frizzled. Science. 2012;337:59-64.
Not in our library10.1126/science.1222879
16.
Zhang X, Dong S, Xu F. Structural and druggability landscape of Frizzled G protein-coupled receptors. Trends Biochem. Sci. 2018;43:1033-1046.
Not in our library10.1016/j.tibs.2018.09.002
17.
Grainger, S. & Willert, K. Mechanisms of Wnt signaling and control. Wiley Interdiscip. Rev. Syst. Biol. Med. e1422, 10.1002/wsbm.1422 (2018).
Not in our library10.1002/wsbm.1422
18.
MacDonald BT, He X. Frizzled and LRP5/6 receptors for Wnt/β-catenin signaling. Cold Spring Harb. Perspect. Biol. 2012;4:a007880.
Not in our library10.1101/cshperspect.a007880
19.
Brennan K, Gonzalez-Sancho JM, Castelo-Soccio LA, Howe LR, Brown AMC. Truncated mutants of the putative Wnt receptor LRP6/Arrow can stabilize beta-catenin independently of Frizzled proteins. Oncogene. 2004;23:4873-4884.
Not in our library10.1038/sj.onc.1207642
20.
de Lau WB, Snel B, Clevers HC. The R-spondin protein family. Genome Biol. 2012;13:242.
Not in our library10.1186/gb-2012-13-3-242
21.
Carmon KS, Gong X, Lin Q, Thomas A, Liu Q. R-spondins function as ligands of the orphan receptors LGR4 and LGR5 to regulate Wnt/beta-catenin signaling. Proc. Natl Acad. Sci. USA. 2011;108:11452-11457.
Not in our library10.1073/pnas.1106083108
22.
Glinka A, et al. LGR4 and LGR5 are R-spondin receptors mediating Wnt/β-catenin and Wnt/PCP signalling. EMBO Rep. 2011;12:1055-1061.
Not in our library10.1038/embor.2011.175
23.
de Lau W, et al. Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling. Nature. 2011;476:293-297.
Not in our library10.1038/nature10337
24.
R-Spondin Potentiates Wnt/β-Catenin Signaling through Orphan Receptors LGR4 and LGR5 · 2012
No notice
25.
Structural and molecular basis of ZNRF3/RNF43 transmembrane ubiquitin ligase inhibition by the Wnt agonist R-spondin · 2013
No notice
26.
Hao H-X, et al. ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner. Nature. 2012;485:195-200.
Not in our library10.1038/nature11019
27.
Koo B-K, et al. Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors. Nature. 2012;488:665-669.
Not in our library10.1038/nature11308
28.
Sharma M, Castro-Piedras I, Simmons GE, Pruitt K. Dishevelled: a masterful conductor of complex Wnt signals. Cell. Signal. 2018;47:52-64.
Not in our library10.1016/j.cellsig.2018.03.004
29.
Schwarz-Romond T, et al. The DIX domain of dishevelled confers Wnt signaling by dynamic polymerization. Nat. Struct. Mol. Biol. 2007;14:484-492.
Not in our library10.1038/nsmb1247
30.
Wong H-C, et al. Direct binding of the PDZ domain of dishevelled to a conserved internal sequence in the C-terminal region of Frizzled. Mol. Cell. 2003;12:1251-1260.
Not in our library10.1016/s1097-2765(03)00427-1
31.
Aberle H, Bauer A, Stappert J, Kispert A, Kemler R. Beta-catenin is a target for the ubiquitin-proteasome pathway. EMBO J. 1997;16:3797-3804.
Not in our library10.1093/emboj/16.13.3797
32.
Valenta T, Hausmann G, Basler K. The many faces and functions of β-catenin. EMBO J. 2012;31:2714-2736.
Not in our library10.1038/emboj.2012.150
33.
Xing Y, Clements WK, Kimelman D, Xu W. Crystal structure of a beta-catenin/axin complex suggests a mechanism for the beta-catenin destruction complex. Genes Dev. 2003;17:2753-2764.
Not in our library10.1101/gad.1142603
34.
Nc, H., T, T., Jl, S., Hj, C. & Wi, W. Mechanism of phosphorylation-dependent binding of APC to beta-catenin and its role in beta-catenin degradation. Mol. Cell15, 511–521 (2004).
Not in our library10.1016/j.molcel.2004.08.010
35.
Graham TA, Weaver C, Mao F, Kimelman D, Xu W. Crystal structure of a beta-catenin/Tcf complex. Cell. 2000;103:885-896.
Not in our library10.1016/s0092-8674(00)00192-6
36.
Gao X, Hannoush RN. Single-cell imaging of Wnt palmitoylation by the acyltransferase porcupine. Nat. Chem. Biol. 2014;10:61-68.
Not in our library10.1038/nchembio.1392
37.
Galli LM, Zebarjadi N, Li L, Lingappa VR, Burrus LW. Divergent effects of porcupine and Wntless on WNT1 trafficking, secretion, and signaling. Exp. Cell Res. 2016;347:171-183.
Not in our library10.1016/j.yexcr.2016.07.028
38.
Ho SY, Keller TH. The use of porcupine inhibitors to target Wnt-driven cancers. Bioorg. Med. Chem. Lett. 2015;25:5472-5476.
Not in our library10.1016/j.bmcl.2015.10.032
39.
Chiang K-C, et al. WNT-1 inducible signaling pathway protein-1 enhances growth and tumorigenesis in human breast cancer. Sci. Rep. 2015;5:8686.
Not in our library10.1038/srep08686
40.
He B, et al. Blockade of Wnt-1 signaling induces apoptosis in human colorectal cancer cells containing downstream mutations. Oncogene. 2005;24:3054-3058.
Not in our library10.1038/sj.onc.1208511
41.
Lv J, et al. M2-like tumor-associated macrophages-secreted Wnt1 and Wnt3a promotes dedifferentiation and metastasis via activating β-catenin pathway in thyroid cancer. Mol. Carcinog. 2021;60:25-37.
Not in our library10.1002/mc.23268
42.
Mizushima T, et al. Wnt-1 but not epidermal growth factor induces beta-catenin/T-cell factor-dependent transcription in esophageal cancer cells. Cancer Res. 2002;62:277-282.
Not in our library
43.
Nakashima T, et al. Wnt1 overexpression associated with tumor proliferation and a poor prognosis in non-small cell lung cancer patients. Oncol. Rep. 2008;19:203-209.
Not in our library
44.
Akalay I, et al. Targeting WNT1-inducible signaling pathway protein 2 alters human breast cancer cell susceptibility to specific lysis through regulation of KLF-4 and miR-7 expression. Oncogene. 2015;34:2261-2271.
Not in our library10.1038/onc.2014.151
45.
Benad P, Rauner M, Rachner TD, Hofbauer LC. The anti-progestin RU-486 inhibits viability of MCF-7 breast cancer cells by suppressing WNT1. Cancer Lett. 2011;312:101-108.
Not in our library10.1016/j.canlet.2011.08.006
46.
Cha Y, et al. MicroRNA-140-5p suppresses cell proliferation and invasion in gastric cancer by targeting WNT1 in the WNT/β-catenin signaling pathway. Oncol. Lett. 2018;16:6369-6376.
Not in our library10.3892/ol.2018.9480
47.
Chang L-C, et al. Identification of a new class of WNT1 inhibitor: cancer cells migration, G-quadruplex stabilization and target validation. Oncotarget. 2016;7:67986-68001.
Not in our library10.18632/oncotarget.6622
48.
Choi A-R, et al. Inhibition of Wnt1 expression reduces the enrichment of cancer stem cells in a mouse model of breast cancer. Biochem. Biophys. Res. Commun. 2012;425:436-442.
Not in our library10.1016/j.bbrc.2012.07.120
49.
Debies MT, et al. Tumor escape in a Wnt1-dependent mouse breast cancer model is enabled by p19Arf/p53 pathway lesions but not p16 Ink4a loss. J. Clin. Invest. 2008;118:51-63.
Not in our library10.1172/jci33320
50.
Huguet EL, McMahon JA, McMahon AP, Bicknell R, Harris AL. Differential expression of human Wnt genes 2, 3, 4, and 7B in human breast cell lines and normal and disease states of human breast tissue. Cancer Res. 1994;54:2615-2621.
Not in our library
51.
Vider BZ, et al. Evidence for the involvement of the Wnt 2 gene in human colorectal cancer. Oncogene. 1996;12:153-158.
Not in our library
52.
Cancer-associated fibroblast-derived WNT2 increases tumor angiogenesis in colon cancer · 2019
No notice
53.
Jiang H, et al. Activation of the Wnt pathway through Wnt2 promotes metastasis in pancreatic cancer. Am. J. Cancer Res. 2014;4:537-544.
Not in our library
54.
Kramer N, et al. Autocrine WNT2 signaling in fibroblasts promotes colorectal cancer progression. Oncogene. 2017;36:5460-5472.
Not in our library10.1038/onc.2017.144
55.
Zhang Z, Wang J, Dong X. Wnt2 contributes to the progression of gastric cancer by promoting cell migration and invasion. Oncol. Lett. 2018;16:2857-2864.
Not in our library10.3892/ol.2018.9050
56.
Xu Y, et al. Wnt2 protein plays a role in the progression of pancreatic cancer promoted by pancreatic stellate cells. Med. Oncol. Northwood Lond. Engl. 2015;32:97.
Not in our library10.1007/s12032-015-0513-2
57.
Lee S-B, Park YI, Dong M-S, Gong Y-D. Identification of 2,3,6-trisubstituted quinoxaline derivatives as a Wnt2/β-catenin pathway inhibitor in non-small-cell lung cancer cell lines. Bioorg. Med. Chem. Lett. 2010;20:5900-5904.
Not in our library10.1016/j.bmcl.2010.07.088
58.
Xiu D-H, et al. Long non-coding RNA LINC00968 attenuates drug resistance of breast cancer cells through inhibiting the Wnt2/β-catenin signaling pathway by regulating WNT2. J. Exp. Clin. Cancer Res. 2019;38:94.
Not in our library10.1186/s13046-019-1100-8
59.
Dale TC, et al. Compartment switching of WNT-2 expression in human breast tumors. Cancer Res. 1996;56:4320-4323.
Not in our library
60.
Katoh M. Molecular cloning and characterization of human WNT3. Int. J. Oncol. 2001;19:977-982.
Not in our library10.3892/ijo.19.5.977
61.
Nie X, et al. Downregulation of Wnt3 suppresses colorectal cancer development through inhibiting cell proliferation and migration. Front. Pharmacol. 2019;10:1110.
Not in our library10.3389/fphar.2019.01110
62.
Wu Y, et al. Expression of Wnt3 activates Wnt/β-catenin pathway and promotes EMT-like phenotype in trastuzumab-resistant HER2-overexpressing breast cancer cells. Mol. Cancer Res. 2012;10:1597-1606.
Not in our library10.1158/1541-7786.mcr-12-0155-t
63.
Wu Y, et al. A83-01 inhibits TGF-β-induced upregulation of Wnt3 and epithelial to mesenchymal transition in HER2-overexpressing breast cancer cells. Breast Cancer Res. Treat. 2017;163:449-460.
Not in our library10.1007/s10549-017-4211-y
64.
Nakashima N, et al. Wnt3 gene expression promotes tumor progression in non-small cell lung cancer. Lung Cancer Amst. Neth. 2012;76:228-234.
Not in our library10.1016/j.lungcan.2011.10.007
65.
Xing Z, et al. Wnt3 knockdown sensitizes human non-small cell type lung cancer (NSCLC) cells to cisplatin via regulating the cell proliferation and apoptosis. Eur. Rev. Med. Pharmacol. Sci. 2018;22:1323-1332.
Not in our library10.26355/eurrev_201803_14474
66.
Ye J, et al. TROAP regulates prostate cancer progression via the WNT3/survivin signalling pathways. Oncol. Rep. 2019;41:1169-1179.
Not in our library10.3892/or.2018.6854
67.
Chu Y, et al. miR-1247-5p functions as a tumor suppressor in human hepatocellular carcinoma by targeting Wnt3. Oncol. Rep. 2017;38:343-351.
Not in our library10.3892/or.2017.5702
68.
Pashirzad M, et al. Role of Wnt3a in the pathogenesis of cancer, current status and prospective. Mol. Biol. Rep. 2019;46:5609-5616.
Not in our library10.1007/s11033-019-04895-4
69.
Zhang C, Wang Y. Metformin attenuates cells stemness and epithelial‑mesenchymal transition in colorectal cancer cells by inhibiting the Wnt3a/β‑catenin pathway. Mol. Med. Rep. 2019;19:1203-1209.
Not in our library10.3892/mmr.2018.9765
70.
Lee MA, et al. Wnt3a expression is associated with MMP-9 expression in primary tumor and metastatic site in recurrent or stage IV colorectal cancer. BMC Cancer. 2014;14:125.
Not in our library10.1186/1471-2407-14-125
71.
Kang, D. W. & Min, D. S. Positive feedback regulation between phospholipase D and Wnt signaling promotes Wnt-driven anchorage-independent growth of colorectal cancer cells. PLoS ONE5, e12109 (2010).
Not in our library10.1371/journal.pone.0012109
72.
Gui S, et al. Wnt3a regulates proliferation, apoptosis and function of pancreatic NIT-1 beta cells via activation of IRS2/PI3K signaling. J. Cell. Biochem. 2013;114:1488-1497.
Not in our library10.1002/jcb.24490
73.
Matei N, et al. Intranasal wnt3a attenuates neuronal apoptosis through Frz1/PIWIL1a/FOXM1 pathway in MCAO rats. J. Neurosci. 2018;38:6787-6801.
Not in our library10.1523/jneurosci.2352-17.2018
74.
Doubravská L, et al. Wnt-expressing rat embryonic fibroblasts suppress Apo2L/TRAIL-induced apoptosis of human leukemia cells. Apoptosis. 2008;13:573-587.
Not in our library10.1007/s10495-008-0191-z
75.
Nygren MK, et al. Wnt3A activates canonical Wnt signalling in acute lymphoblastic leukaemia (ALL) cells and inhibits the proliferation of B-ALL cell lines. Br. J. Haematol. 2007;136:400-413.
Not in our library10.1111/j.1365-2141.2006.06442.x
76.
Aripaka K, et al. TRAF6 function as a novel co-regulator of Wnt3a target genes in prostate cancer. EBioMedicine. 2019;45:192-207.
Not in our library10.1016/j.ebiom.2019.06.046
77.
Moon YH, Lim W, Jeong B-C. Transmembrane protein 64 modulates prostate tumor progression by regulating Wnt3a secretion. Oncol. Lett. 2019;18:283-290.
Not in our library10.3892/ol.2019.10324
78.
Yang Y, et al. MicroRNA‑214 targets Wnt3a to suppress liver cancer cell proliferation. Mol. Med. Rep. 2017;16:6920-6927.
Not in our library10.3892/mmr.2017.7483
79.
Yang Y, et al. MicroRNA-195 acts as a tumor suppressor by directly targeting Wnt3a in HepG2 hepatocellular carcinoma cells. Mol. Med. Rep. 2014;10:2643-2648.
Not in our library10.3892/mmr.2014.2526
80.
Schenkelaars Q, Fierro-Constain L, Renard E, Hill AL, Borchiellini C. Insights into Frizzled evolution and new perspectives. Evol. Dev. 2015;17:160-169.
Not in our library10.1111/ede.12115
81.
Tauriello DVF, et al. Wnt/β-catenin signaling requires interaction of the Dishevelled DEP domain and C terminus with a discontinuous motif in Frizzled. Proc. Natl Acad. Sci. USA. 2012;109:E812-E820.
Not in our library10.1073/pnas.1114802109
82.
Milovanovic T, et al. Expression of Wnt genes and Frizzled 1 and 2 receptors in normal breast epithelium and infiltrating breast carcinoma. Int. J. Oncol. 2004;25:1337-1342.
Not in our library
83.
Li Y, Lu W, He X, Schwartz AL, Bu G. LRP6 expression promotes cancer cell proliferation and tumorigenesis by altering beta-catenin subcellular distribution. Oncogene. 2004;23:9129-9135.
Not in our library10.1038/sj.onc.1208123
84.
Flanagan DJ, et al. Frizzled-7 is required for Wnt signaling in gastric tumors with and without Apc mutations. Cancer Res. 2019;79:970-981.
Not in our library10.1158/0008-5472.can-18-2095
85.
Sun, Y., Wang, W. & Zhao, C. Frizzled receptors in tumors, focusing on signaling, roles, modulation mechanisms, and targeted therapies. Oncol. Res. 10.3727/096504020X16014648664459 (2020).
Not in our library10.3727/096504020x16014648664459
86.
Gazit A, et al. Human Frizzled 1 interacts with transforming Wnts to transduce a TCF dependent transcriptional response. Oncogene. 1999;18:5959-5966.
Not in our library10.1038/sj.onc.1202985
87.
Wang Z, Shu W, Lu MM, Morrisey EE. Wnt7b activates canonical signaling in epithelial and vascular smooth muscle cells through interactions with Fzd1, Fzd10, and LRP5. Mol. Cell. Biol. 2005;25:5022-5030.
Not in our library10.1128/mcb.25.12.5022-5030.2005
88.
Koval A, Katanaev VL. Wnt3a stimulation elicits G-protein-coupled receptor properties of mammalian Frizzled proteins. Biochem. J. 2011;433:435-440.
Not in our library10.1042/bj20101878
89.
Endo Y, et al. Wnt-3a and Dickkopf-1 stimulate neurite outgrowth in Ewing tumor cells via a Frizzled3- and c-Jun N-terminal kinase-dependent mechanism. Mol. Cell. Biol. 2008;28:2368-2379.
Not in our library10.1128/mcb.01780-07
90.
Hansen C, et al. Wnt-5a-induced phosphorylation of DARPP-32 inhibits breast cancer cell migration in a CREB-dependent manner. J. Biol. Chem. 2009;284:27533-27543.
Not in our library10.1074/jbc.m109.048884
91.
Mo D, et al. A tRNA fragment, 5’-tiRNAVal, suppresses the Wnt/β-catenin signaling pathway by targeting FZD3 in breast cancer. Cancer Lett. 2019;457:60-73.
Not in our library10.1016/j.canlet.2019.05.007
92.
Gupta S, et al. FZD4 as a mediator of ERG oncogene-induced WNT signaling and epithelial-to-mesenchymal transition in human prostate cancer cells. Cancer Res. 2010;70:6735-6745.
Not in our library10.1158/0008-5472.can-10-0244
93.
Thiele S, et al. Role of WNT5A receptors FZD5 and RYK in prostate cancer cells. Oncotarget. 2018;9:27293-27304.
Not in our library10.18632/oncotarget.25551
94.
Dong D, et al. FZD5 prevents epithelial-mesenchymal transition in gastric cancer. Cell Commun. Signal. 2021;19:21.
Not in our library10.1186/s12964-021-00708-z
95.
Rubinfeld B, et al. Binding of GSK3beta to the APC-beta-catenin complex and regulation of complex assembly. Science. 1996;272:1023-1026.
Not in our library10.1126/science.272.5264.1023
96.
Corda G, et al. Functional and prognostic significance of the genomic amplification of Frizzled 6 (FZD6) in breast cancer. J. Pathol. 2017;241:350-361.
Not in our library10.1002/path.4841
97.
King TD, Zhang W, Suto MJ, Li Y. Frizzled7 as an emerging target for cancer therapy. Cell. Signal. 2012;24:846-851.
Not in our library10.1016/j.cellsig.2011.12.009
98.
Kim M, et al. Functional interaction between Wnt3 and Frizzled-7 leads to activation of the Wnt/beta-catenin signaling pathway in hepatocellular carcinoma cells. J. Hepatol. 2008;48:780-791.
Not in our library10.1016/j.jhep.2007.12.020
99.
Chakravarthi BVSK, et al. Wnt receptor Frizzled 8 is a target of ERG in prostate cancer. Prostate. 2018;78:1311-1320.
Not in our library10.1002/pros.23704
100.
Scavo MP, et al. Frizzled-10 and cancer progression: Is it a new prognostic marker? Oncotarget. 2018;9:824-830.
Not in our library10.18632/oncotarget.23159
101.
Nagayama S, et al. Therapeutic potential of antibodies against FZD10, a cell-surface protein, for synovial sarcomas. Oncogene. 2005;24:6201-6212.
Not in our library10.1038/sj.onc.1208780
102.
Liu, Z. et al. Hypoxia-induced suppression of alternative splicing of MBD2 promotes breast cancer metastasis via activation of FZD1. Cancer Res. 10.1158/0008-5472.CAN-20-2876 (2021).
Not in our library10.1158/0008-5472.can-20-2876
103.
Zhang H, et al. Interference of Frizzled 1 (FZD1) reverses multidrug resistance in breast cancer cells through the Wnt/β-catenin pathway. Cancer Lett. 2012;323:106-113.
Not in our library10.1016/j.canlet.2012.03.039
104.
Su W, et al. miR-135b reverses chemoresistance of non-small cell lung cancer cells by downregulation of FZD1. Biomed. Pharmacother. Biomedecine Pharmacother. 2016;84:123-129.
Not in our library10.1016/j.biopha.2016.09.027
105.
Zhang H, et al. Suppression of multidrug resistance by rosiglitazone treatment in human ovarian cancer cells through downregulation of FZD1 and MDR1 genes. Anticancer. Drugs. 2015;26:706-715.
Not in our library10.1097/cad.0000000000000236
106.
Li, H. et al. WITHDRAWN: MicroRNA-505 modulates cancer proliferation and migration in human non-small cell lung cancer through inverse regulation of FZD4. Lung Cancer Amst. Neth. 10.1016/j.lungcan.2017.03.016 (2017).
Not in our library10.1016/j.lungcan.2017.03.016
107.
Ueno K, et al. Tumor suppressor microRNA-493 decreases cell motility and migration ability in human bladder cancer cells by downregulating RhoC and FZD4. Mol. Cancer Ther. 2012;11:244-253.
Not in our library10.1158/1535-7163.mct-11-0592
108.
Wang Y, Zhang W, Wang Y, Wang S. HOXD-AS1 promotes cell proliferation, migration and invasion through miR-608/FZD4 axis in ovarian cancer. Am. J. Cancer Res. 2018;8:170-182.
Not in our library
109.
Frizzled-7 as a Potential Therapeutic Target in Colorectal Cancer · 2008
Not checked
110.
Fenderico N, et al. Anti-LRP5/6 VHHs promote differentiation of Wnt-hypersensitive intestinal stem cells. Nat. Commun. 2019;10:365.
Not in our library10.1038/s41467-018-08172-z
111.
An LRP5 receptor with internal deletion in hyperparathyroid tumors with implications for deregulated WNT/beta-catenin signaling. · 2007
Not checked
112.
Wang H, et al. Hsp90ab1 stabilizes LRP5 to promote epithelial-mesenchymal transition via activating of AKT and Wnt/β-catenin signaling pathways in gastric cancer progression. Oncogene. 2019;38:1489-1507.
Not in our library10.1038/s41388-018-0532-5
113.
Q, Y. et al. LRP6 promotes invasion and metastasis of colorectal cancer through cytoskeleton dynamics. Oncotarget8, 109632–109645 (2017).
Not in our library10.18632/oncotarget.22759
114.
Liu C-C, Prior J, Piwnica-Worms D, Bu G. LRP6 overexpression defines a class of breast cancer subtype and is a target for therapy. Proc. Natl Acad. Sci. USA. 2010;107:5136-5141.
Not in our library10.1073/pnas.0911220107
115.
Tahir SA, et al. Caveolin-1-LRP6 signaling module stimulates aerobic glycolysis in prostate cancer. Cancer Res. 2013;73:1900-1911.
Not in our library10.1158/0008-5472.can-12-3040
116.
Ettenberg SA, et al. Inhibition of tumorigenesis driven by different Wnt proteins requires blockade of distinct ligand-binding regions by LRP6 antibodies. Proc. Natl Acad. Sci. USA. 2010;107:15473-15478.
Not in our library10.1073/pnas.1007428107
117.
R-spondins can potentiate WNT signaling without LGRs · 2018
No notice
118.
Szenker-Ravi E, et al. RSPO2 inhibition of RNF43 and ZNRF3 governs limb development independently of LGR4/5/6. Nature. 2018;557:564-569.
Not in our library10.1038/s41586-018-0118-y
119.
Seshagiri S, et al. Recurrent R-spondin fusions in colon cancer. Nature. 2012;488:660-664.
Not in our library10.1038/nature11282
120.
Han T, et al. R-Spondin chromosome rearrangements drive Wnt-dependent tumour initiation and maintenance in the intestine. Nat. Commun. 2017;8:15945.
Not in our library10.1038/ncomms15945
121.
Bugter JM, Fenderico N, Maurice MM. Mutations and mechanisms of WNT pathway tumour suppressors in cancer. Nat. Rev. Cancer. 2021;21:5-21.
Not in our library10.1038/s41568-020-00307-z
122.
Ryland GL, et al. RNF43 is a tumour suppressor gene mutated in mucinous tumours of the ovary. J. Pathol. 2013;229:469-476.
Not in our library10.1002/path.4134
123.
Eto T, et al. Impact of loss-of-function mutations at the RNF43 locus on colorectal cancer development and progression. J. Pathol. 2018;245:445-455.
Not in our library10.1002/path.5098
124.
Jiang X, et al. Inactivating mutations of RNF43 confer Wnt dependency in pancreatic ductal adenocarcinoma. Proc. Natl Acad. Sci. USA. 2013;110:12649-12654.
Not in our library10.1073/pnas.1307218110
125.
Kleeman, S. O. et al. Exploiting differential Wnt target gene expression to generate a molecular biomarker for colorectal cancer stratification. Gut69, 1092–1103 (2020).
Not in our library10.1136/gutjnl-2019-319126
126.
Li S, et al. Commonly observed RNF43 mutations retain functionality in attenuating Wnt/β-catenin signaling and unlikely confer Wnt-dependency onto colorectal cancers. Oncogene. 2020;39:3458-3472.
Not in our library10.1038/s41388-020-1232-5
127.
Laurent-Puig P, Béroud C, Soussi T. APC gene: database of germline and somatic mutations in human tumors and cell lines. Nucleic Acids Res. 1998;26:269-270.
Not in our library10.1093/nar/26.1.269
128.
Wachsmannova L, Mego M, Stevurkova V, Zajac V, Ciernikova S. Novel strategies for comprehensive mutation screening of the APC gene. Neoplasma. 2017;64:338-343.
Not in our library10.4149/neo_2017_303
129.
Cao X, Hong Y, Eu KW, Loi C, Cheah PY. Singapore familial adenomatous polyposis (FAP) patients with classical adenomatous polyposis but undetectable APC mutations have accelerated cancer progression. Am. J. Gastroenterol. 2006;101:2810-2817.
Not in our library10.1111/j.1572-0241.2006.00842.x
130.
Aghabozorgi AS, et al. Role of adenomatous polyposis coli (APC) gene mutations in the pathogenesis of colorectal cancer; current status and perspectives. Biochimie. 2019;157:64-71.
Not in our library10.1016/j.biochi.2018.11.003
131.
Aitchison A, et al. APC mutations are not confined to hotspot regions in early-onset colorectal cancer. Cancers. 2020;12:3829.
Not in our library10.3390/cancers12123829
132.
Fodde R. The APC gene in colorectal cancer. Eur. J. Cancer Oxf. Engl. 2002;38:867-871.
Not in our library10.1016/s0959-8049(02)00040-0
133.
A novel GSK3-regulated APC:Axin interaction regulates Wnt signaling by driving a catalytic cycle of efficient βcatenin destruction · 2015
Not checked
134.
Singh I, Pujol A. Pathomechanisms underlying X-adrenoleukodystrophy: a three-hit hypothesis. Brain Pathol. Zur. Switz. 2010;20:838-844.
Not in our library10.1111/j.1750-3639.2010.00392.x
135.
Rosin-Arbesfeld R, Townsley F, Bienz M. The APC tumour suppressor has a nuclear export function. Nature. 2000;406:1009-1012.
Not in our library10.1038/35023016
136.
Zhang L, Shay JW. Multiple roles of APC and its therapeutic implications in colorectal cancer. J. Natl Cancer Inst. 2017;109:djw332.
Not in our library10.1093/jnci/djw332
137.
De Santis, S. et al. Winnie-APCMin/+ mice: a spontaneous model of colitis-associated colorectal cancer combining genetics and inflammation. Int. J. Mol. Sci. 21, 2972 (2020).
Not in our library10.3390/ijms21082972
138.
Wechter WJ, et al. R-flurbiprofen chemoprevention and treatment of intestinal adenomas in the APC(Min)/+ mouse model: implications for prophylaxis and treatment of colon cancer. Cancer Res. 1997;57:4316-4324.
Not in our library
139.
Irving AA, et al. The utility of Apc-mutant rats in modeling human colon cancer. Dis. Model. Mech. 2014;7:1215-1225.
Not in our library10.1242/dmm.016980
140.
Ohgaki H, et al. APC mutations are infrequent but present in human lung cancer. Cancer Lett. 2004;207:197-203.
Not in our library10.1016/j.canlet.2003.10.020
141.
Thompson AM, et al. Allele loss from 5q21 (APC/MCC) and 18q21 (DCC) and DCC mRNA expression in breast cancer. Br. J. Cancer. 1993;68:64-68.
Not in our library10.1038/bjc.1993.287
142.
Jönsson M, Borg A, Nilbert M, Andersson T. Involvement of adenomatous polyposis coli (APC)/beta-catenin signalling in human breast cancer. Eur. J. Cancer Oxf. Engl. 2000;36:242-248.
Not in our library10.1016/s0959-8049(99)00276-2
143.
McKie AB, Filipe MI, Lemoine NR. Abnormalities affecting the APC and MCC tumour suppressor gene loci on chromosome 5q occur frequently in gastric cancer but not in pancreatic cancer. Int. J. Cancer. 1993;55:598-603.
Not in our library10.1002/ijc.2910550414
144.
Gao X, et al. High-frequency of loss of expression and allelic deletion of the apc and mcc genes in human prostate-cancer. Int. J. Oncol. 1995;6:111-117.
Not in our library10.3892/ijo.6.1.111
145.
Guo S, et al. Quantitative assessment of the diagnostic role of APC promoter methylation in non-small cell lung cancer. Clin. Epigenet. 2014;6:5.
Not in our library10.1186/1868-7083-6-5
146.
Chen Y, et al. APC gene hypermethylation and prostate cancer: a systematic review and meta-analysis. Eur. J. Hum. Genet. 2013;21:929-935.
Not in our library10.1038/ejhg.2012.281
147.
Ikeda S, et al. Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3beta and beta-catenin and promotes GSK-3beta-dependent phosphorylation of beta-catenin. EMBO J. 1998;17:1371-1384.
Not in our library10.1093/emboj/17.5.1371
148.
Bridging of β-catenin and glycogen synthase kinase-3β by Axin and inhibition of β-catenin-mediated transcription · 1998
Not checked
149.
Noutsou M, et al. Critical scaffolding regions of the tumor suppressor Axin1 are natively unfolded. J. Mol. Biol. 2011;405:773-786.
Not in our library10.1016/j.jmb.2010.11.013
150.
Spink KE, Polakis P, Weis WI. Structural basis of the Axin-adenomatous polyposis coli interaction. EMBO J. 2000;19:2270-2279.
Not in our library10.1093/emboj/19.10.2270
151.
Schwarz-Romond T. The DIX domain of Dishevelled confers Wnt signaling by dynamic polymerization. Nat. Struct. Mol. Biol. 2007;14:484-492.
Not in our library10.1038/nsmb1247
152.
Dajani R, et al. Structural basis for recruitment of glycogen synthase kinase 3beta to the axin-APC scaffold complex. EMBO J. 2003;22:494-501.
Not in our library10.1093/emboj/cdg068
153.
Anvarian Z, et al. Axin cancer mutants form nanoaggregates to rewire the Wnt signaling network. Nat. Struct. Mol. Biol. 2016;23:324-332.
Not in our library10.1038/nsmb.3191
154.
Cha P-H, et al. Small-molecule binding of the axin RGS domain promotes β-catenin and Ras degradation. Nat. Chem. Biol. 2016;12:593-600.
Not in our library10.1038/nchembio.2103
155.
An aggregon in conductin/axin2 regulates Wnt/β-catenin signaling and holds potential for cancer therapy · 2019
Not checked
156.
Satoh S, et al. AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1. Nat. Genet. 2000;24:245-250.
Not in our library10.1038/73448
157.
Boyault S, et al. Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology. 2007;45:42-52.
Not in our library10.1002/hep.21467
158.
Feng GJ, et al. Conditional disruption of Axin1 leads to development of liver tumors in mice. Gastroenterology. 2012;143:1650-1659.
Not in our library10.1053/j.gastro.2012.08.047
159.
Qiao Y, et al. Axis inhibition protein 1 (Axin1) deletion-induced hepatocarcinogenesis requires intact β-catenin but not notch cascade in mice. Hepatology. 2019;70:2003-2017.
Not in our library10.1002/hep.30556
160.
Picco G, et al. Loss of AXIN1 drives acquired resistance to WNT pathway blockade in colorectal cancer cells carrying RSPO3 fusions. EMBO Mol. Med. 2017;9:293-303.
Not in our library10.15252/emmm.201606773
161.
Syed SM, Tanwar PS. Axin2+ endometrial stem cells: the source of endometrial regeneration and cancer. Mol. Cell. Oncol. 2020;7:1729681.
Not in our library10.1080/23723556.2020.1729681
162.
Lammi L, et al. Mutations in AXIN2 cause familial tooth agenesis and predispose to colorectal cancer. Am. J. Hum. Genet. 2004;74:1043-1050.
Not in our library10.1086/386293
163.
Liu W, et al. Mutations in AXIN2 cause colorectal cancer with defective mismatch repair by activating beta-catenin/TCF signalling. Nat. Genet. 2000;26:146-147.
Not in our library10.1038/79859
164.
Otero L, et al. Variations in AXIN2 predict risk and prognosis of colorectal cancer. BDJ Open. 2019;5:13.
Not in our library10.1038/s41405-019-0022-z
165.
Rosales-Reynoso MA, et al. AXIN2 polymorphisms and their association with colorectal cancer in mexican patients. Genet. Test. Mol. Biomark. 2016;20:438-444.
Not in our library10.1089/gtmb.2016.0026
166.
Bahl, C., Sharma, S., Singh, N. & Behera, D. Association study between genetic variations in Axin2 gene and lung cancer risk in North Indian population: a multiple interaction analysis. Tumour Biol. J. Int. Soc. Oncodevelopmental Biol. Med. 39, 1010428317695533 (2017).
Not in our library10.1177/1010428317695533
167.
Hughes TA, Brady HJM. Regulation of axin2 expression at the levels of transcription, translation and protein stability in lung and colon cancer. Cancer Lett. 2006;233:338-347.
Not in our library10.1016/j.canlet.2005.03.026
168.
Aristizabal-Pachon AF, Carvalho TI, Carrara HH, Andrade J, Takahashi CS. AXIN2 polymorphisms, the β-catenin destruction complex expression profile and breast cancer susceptibility. Asian Pac. J. Cancer Prev. 2015;16:7277-7284.
Not in our library10.7314/apjcp.2015.16.16.7277
169.
Inhibition of Tankyrases Induces Axin Stabilization and Blocks Wnt Signalling in Breast Cancer Cells · 2012
No notice
170.
Dai J, Gao H, Xue J, Lin W, Zheng L. The association between AXIN2 gene polymorphisms and the risk of breast cancer in chinese women. Genet. Test. Mol. Biomark. 2019;23:393-400.
Not in our library10.1089/gtmb.2018.0309
171.
Huang S-MA, et al. Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature. 2009;461:614-620.
Not in our library10.1038/nature08356
172.
Gibson BA, Kraus WL. New insights into the molecular and cellular functions of poly(ADP-ribose) and PARPs. Nat. Rev. Mol. Cell Biol. 2012;13:411-424.
Not in our library10.1038/nrm3376
173.
Haikarainen T, Krauss S, Lehtiö L. Tankyrases: structure, function and therapeutic implications in cancer. Curr. Pharm. Des. 2014;20:6472-6488.
Not in our library10.2174/1381612820666140630101525
174.
Zhang Y, et al. RNF146 is a poly(ADP-ribose)-directed E3 ligase that regulates axin degradation and Wnt signalling. Nat. Cell Biol. 2011;13:623-629.
Not in our library10.1038/ncb2222
175.
Wang Z, et al. Wnt/Wingless pathway activation is promoted by a critical threshold of axin maintained by the tumor suppressor APC and the ADP-ribose polymerase tankyrase. Genetics. 2016;203:269-281.
Not in our library10.1534/genetics.115.183244
176.
Yang E, et al. Wnt pathway activation by ADP-ribosylation. Nat. Commun. 2016;7:11430.
Not in our library10.1038/ncomms11430
177.
Wang, W., Tacchelly-Benites, O., Yang, E. & Ahmed, Y. Dual roles for membrane association of Drosophila axin in Wnt signaling. PLoS Genet.12, e1006494 (2016).
Not in our library10.1371/journal.pgen.1006494
178.
Regulation of Wnt/β‐catenin signalling by tankyrase‐dependent poly(ADP‐ribosyl)ation and scaffolding · 2017
No notice
179.
Riffell JL, Lord CJ, Ashworth A. Tankyrase-targeted therapeutics: expanding opportunities in the PARP family. Nat. Rev. Drug Discov. 2012;11:923-936.
Not in our library10.1038/nrd3868
180.
Kamal A, Riyaz S, Srivastava AK, Rahim A. Tankyrase inhibitors as therapeutic targets for cancer. Curr. Top. Med. Chem. 2014;14:1967-1976.
Not in our library10.2174/1568026614666140929115831
181.
Cormier, K. W. & Woodgett, J. R. Recent advances in understanding the cellular roles of GSK-3. F1000Research6, 167 (2017).
Not in our library10.12688/f1000research.10557.1
182.
Yuan H, Mao J, Li L, Wu D. Suppression of glycogen synthase kinase activity is not sufficient for leukemia enhancer factor-1 activation. J. Biol. Chem. 1999;274:30419-30423.
Not in our library10.1074/jbc.274.43.30419
183.
Zheng X, et al. A dual-kinase mechanism for Wnt co-receptor phosphorylation and activation. Nature. 2005;438:873-877.
Not in our library10.1038/nature04185
184.
Zeng, X. et al. Initiation of Wnt signaling: control of Wnt coreceptor Lrp6 phosphorylation/activation via frizzled, dishevelled and axin functions. Development135, 367–375 (2008).
Not in our library10.1242/dev.013540
185.
Davidson G, et al. Casein kinase 1 gamma couples Wnt receptor activation to cytoplasmic signal transduction. Nature. 2005;438:867-872.
Not in our library10.1038/nature04170
186.
Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR Cascade Inhibitors: How Mutations Can Result in Therapy Resistance and How to Overcome Resistance · 2012
No notice
187.
Medunjanin S, et al. GSK-3β controls NF-kappaB activity via IKKγ/NEMO. Sci. Rep. 2016;6:38553.
Not in our library10.1038/srep38553
188.
Liu C, et al. Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell. 2002;108:837-847.
Not in our library10.1016/s0092-8674(02)00685-2
189.
Knippschild U, et al. The casein kinase 1 family: participation in multiple cellular processes in eukaryotes. Cell. Signal. 2005;17:675-689.
Not in our library10.1016/j.cellsig.2004.12.011
190.
Cruciat, C. M. Casein kinase 1 and Wnt/β-catenin signaling. Curr. Opin. Cell Biol. 31, 46–55 (2014).
Not in our library10.1016/j.ceb.2014.08.003
191.
Xing Y, et al. Crystal structure of a beta-catenin/APC complex reveals a critical role for APC phosphorylation in APC function. Mol. Cell. 2004;15:523-533.
Not in our library10.1016/j.molcel.2004.08.001
192.
de Groot REA, et al. Huwe1-mediated ubiquitylation of dishevelled defines a negative feedback loop in the Wnt signaling pathway. Sci. Signal. 2014;7:ra26.
Not in our library10.1126/scisignal.2004985
193.
Bilic J, et al. Wnt induces LRP6 signalosomes and promotes dishevelled-dependent LRP6 phosphorylation. Science. 2007;316:1619-1622.
Not in our library10.1126/science.1137065
194.
Thorne CA, et al. Small-molecule inhibition of Wnt signaling through activation of casein kinase 1α. Nat. Chem. Biol. 2010;6:829-836.
Not in our library10.1038/nchembio.453
195.
Lee E, Salic A, Kirschner MW. Physiological regulation of [beta]-catenin stability by Tcf3 and CK1epsilon. J. Cell Biol. 2001;154:983-993.
Not in our library10.1083/jcb.200102074
196.
Kishida S, et al. DIX domains of Dvl and axin are necessary for protein interactions and their ability to regulate beta-catenin stability. Mol. Cell. Biol. 1999;19:4414-4422.
Not in our library10.1128/mcb.19.6.4414
197.
Gao, C. & Chen, Y. G. Dishevelled: the hub of Wnt signaling. Cell. Signal. 22, 717–727 (2010).
Not in our library10.1016/j.cellsig.2009.11.021
198.
Habas R, Dawid IB. Dishevelled and Wnt signaling: is the nucleus the final frontier? J. Biol. 2005;4:2.
Not in our library10.1186/jbiol22
199.
Nuclear localization is required for Dishevelled function in Wnt/β-catenin signaling · 2005
No notice
200.
Luo W, et al. Protein phosphatase 1 regulates assembly and function of the beta-catenin degradation complex. EMBO J. 2007;26:1511-1521.
Not in our library10.1038/sj.emboj.7601607
201.
Strovel ET, Wu D, Sussman DJ. Protein phosphatase 2Calpha dephosphorylates axin and activates LEF-1-dependent transcription. J. Biol. Chem. 2000;275:2399-2403.
Not in our library10.1074/jbc.275.4.2399
202.
Cho US, Xu W. Crystal structure of a protein phosphatase 2A heterotrimeric holoenzyme. Nature. 2007;445:53-57.
Not in our library10.1038/nature05351
203.
Janssens V, Longin S, Goris J. PP2A holoenzyme assembly: in cauda venenum (the sting is in the tail). Trends Biochem. Sci. 2008;33:113-121.
Not in our library10.1016/j.tibs.2007.12.004
204.
Virshup DM. Protein phosphatase 2A: a panoply of enzymes. Curr. Opin. Cell Biol. 2000;12:180-185.
Not in our library10.1016/s0955-0674(99)00074-5
205.
Zhang W, et al. PR55 alpha, a regulatory subunit of PP2A, specifically regulates PP2A-mediated beta-catenin dephosphorylation. J. Biol. Chem. 2009;284:22649-22656.
Not in our library10.1074/jbc.m109.013698
206.
Yu, N. et al. HSP105 recruits protein phosphatase 2A to dephosphorylate β-catenin. Mol. Cell. Biol.35, 1390–1400 (2015).
Not in our library10.1128/mcb.01307-14
207.
Su Y, et al. APC is essential for targeting phosphorylated beta-catenin to the SCFbeta-TrCP ubiquitin ligase. Mol. Cell. 2008;32:652-661.
Not in our library10.1016/j.molcel.2008.10.023
208.
Johnson V, et al. Exon 3 beta-catenin mutations are specifically associated with colorectal carcinomas in hereditary non-polyposis colorectal cancer syndrome. Gut. 2005;54:264-267.
Not in our library10.1136/gut.2004.048132
209.
Morin PJ, et al. Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science. 1997;275:1787-1790.
Not in our library10.1126/science.275.5307.1787
210.
Abdelmaksoud-Damak R, et al. Expression and mutation pattern of β-catenin and adenomatous polyposis coli in colorectal cancer patients. Arch. Med. Res. 2015;46:54-62.
Not in our library10.1016/j.arcmed.2015.01.001
211.
Voeller HJ, Truica CI, Gelmann EP. Beta-catenin mutations in human prostate cancer. Cancer Res. 1998;58:2520-2523.
Not in our library
212.
Ogasawara N, et al. Mutations and nuclear accumulation of beta-catenin correlate with intestinal phenotypic expression in human gastric cancer. Histopathology. 2006;49:612-621.
Not in our library10.1111/j.1365-2559.2006.02560.x
213.
Kizildag S, Zengel B, Vardar E, Sakizli M. beta-catenin gene mutation in invasive ductal breast cancer. J. BUON. 2008;13:533-536.
Not in our library
214.
Roy D, Calaf GM. Mutation of β-catenin in a radiation and estrogen breast cancer model. Int. J. Oncol. 2015;46:153-160.
Not in our library10.3892/ijo.2014.2722
215.
Wright K, et al. beta-catenin mutation and expression analysis in ovarian cancer: exon 3 mutations and nuclear translocation in 16% of endometrioid tumours. Int. J. Cancer. 1999;82:625-629.
Not in our library10.1002/(sici)1097-0215(19990827)82:5<625::aid-ijc1>3.0.co;2-2
216.
Kurnit KC, et al. CTNNB1 (beta-catenin) mutation identifies low grade, early stage endometrial cancer patients at increased risk of recurrence. Mod. Pathol. 2017;30:1032-1041.
Not in our library10.1038/modpathol.2017.15
217.
Takemaru KI, Moon RT. The transcriptional coactivator CBP interacts with beta-catenin to activate gene expression. J. Cell Biol. 2000;149:249-254.
Not in our library10.1083/jcb.149.2.249
218.
Ono M, et al. Nuclear receptor/Wnt beta-catenin interactions are regulated via differential CBP/p300 coactivator usage. PLoS ONE. 2018;13:e0200714.
Not in our library10.1371/journal.pone.0200714
219.
Daniels DL, Weis WI. Beta-catenin directly displaces Groucho/TLE repressors from Tcf/Lef in Wnt-mediated transcription activation. Nat. Struct. Mol. Biol. 2005;12:364-371.
Not in our library10.1038/nsmb912
220.
Hanson AJ, et al. XIAP monoubiquitylates Groucho/TLE to promote canonical Wnt signaling. Mol. Cell. 2012;45:619-628.
Not in our library10.1016/j.molcel.2011.12.032
221.
Jia Y, et al. Thymine DNA glycosylase promotes transactivation of β-catenin/TCFs by cooperating with CBP. J. Mol. Cell Biol. 2014;6:231-239.
Not in our library10.1093/jmcb/mju014
222.
Hecht A, Vleminckx K, Stemmler MP, van Roy F, Kemler R. The p300/CBP acetyltransferases function as transcriptional coactivators of beta-catenin in vertebrates. EMBO J. 2000;19:1839-1850.
Not in our library10.1093/emboj/19.8.1839
223.
Lévy L, et al. Acetylation of beta-catenin by p300 regulates beta-catenin-Tcf4 interaction. Mol. Cell. Biol. 2004;24:3404-3414.
Not in our library10.1128/mcb.24.8.3404-3414.2004
224.
Kramps T, et al. Wnt/wingless signaling requires BCL9/legless-mediated recruitment of pygopus to the nuclear beta-catenin-TCF complex. Cell. 2002;109:47-60.
Not in our library10.1016/s0092-8674(02)00679-7
225.
Bauer A, et al. Pontin52 and reptin52 function as antagonistic regulators of beta-catenin signalling activity. EMBO J. 2000;19:6121-6130.
Not in our library10.1093/emboj/19.22.6121
226.
Barker N, et al. The chromatin remodelling factor Brg-1 interacts with beta-catenin to promote target gene activation. EMBO J. 2001;20:4935-4943.
Not in our library10.1093/emboj/20.17.4935
227.
Rao M, et al. Inhibition of cyclin D1 gene transcription by Brg-1. Cell Cycle. 2008;7:647-655.
Not in our library10.4161/cc.7.5.5446
228.
Mahmoudi T, et al. The leukemia-associated Mllt10/Af10-Dot1l are Tcf4/β-catenin coactivators essential for intestinal homeostasis. PLoS Biol. 2010;8:e1000539.
Not in our library10.1371/journal.pbio.1000539
229.
Zhou D, et al. SOX10 is a novel oncogene in hepatocellular carcinoma through Wnt/β-catenin/TCF4 cascade. Tumour Biol. 2014;35:9935-9940.
Not in our library10.1007/s13277-014-1893-1
230.
Shin S, Rossow KL, Grande JP, Janknecht R. Involvement of RNA helicases p68 and p72 in colon cancer. Cancer Res. 2007;67:7572-7578.
Not in our library10.1158/0008-5472.can-06-4652
231.
Kimbrel EA, Kung AL. The F-box protein beta-TrCp1/Fbw1a interacts with p300 to enhance beta-catenin transcriptional activity. J. Biol. Chem. 2009;284:13033-13044.
Not in our library10.1074/jbc.m901248200
232.
Gong A, Huang S. FoxM1 and Wnt/β-catenin signaling in glioma stem cells. Cancer Res. 2012;72:5658-5662.
Not in our library10.1158/0008-5472.can-12-0953
233.
Pratheeshkumar P, et al. FoxM1 and β-catenin predicts aggressiveness in Middle Eastern ovarian cancer and their co-targeting impairs the growth of ovarian cancer cells. Oncotarget. 2018;9:3590-3604.
Not in our library10.18632/oncotarget.23338
234.
Shukla S, et al. The FOXM1 Inhibitor RCM-1 Decreases Carcinogenesis and Nuclear β-catenin. Mol. Cancer Ther. 2019;18:1217-1229.
Not in our library10.1158/1535-7163.mct-18-0709
235.
Tao J, et al. Activation of β-catenin and Yap1 in human hepatoblastoma and induction of hepatocarcinogenesis in mice. Gastroenterology. 2014;147:690-701.
Not in our library10.1053/j.gastro.2014.05.004
236.
Liu T, et al. The β-catenin/YAP signaling axis is a key regulator of melanoma-associated fibroblasts. Signal Transduct. Target. Ther. 2019;4:63.
Not in our library10.1038/s41392-019-0100-7
237.
Kaidi A, Williams AC, Paraskeva C. Interaction between beta-catenin and HIF-1 promotes cellular adaptation to hypoxia. Nat. Cell Biol. 2007;9:210-217.
Not in our library10.1038/ncb1534
238.
Choi H, Chun Y-S, Kim T-Y, Park J-W. HIF-2alpha enhances beta-catenin/TCF-driven transcription by interacting with beta-catenin. Cancer Res. 2010;70:10101-10111.
Not in our library10.1158/0008-5472.can-10-0505
239.
Sui H, et al. Tanshinone IIA inhibits β-catenin/VEGF-mediated angiogenesis by targeting TGF-β1 in normoxic and HIF-1α in hypoxic microenvironments in human colorectal cancer. Cancer Lett. 2017;403:86-97.
Not in our library10.1016/j.canlet.2017.05.013
240.
Jung C, Kim R-S, Lee S-J, Wang C, Jeng M-H. HOXB13 homeodomain protein suppresses the growth of prostate cancer cells by the negative regulation of T-cell factor 4. Cancer Res. 2004;64:3046-3051.
Not in our library10.1158/0008-5472.can-03-2614
241.
Jung C, et al. HOXB13 is downregulated in colorectal cancer to confer TCF4-mediated transactivation. Br. J. Cancer. 2005;92:2233-2239.
Not in our library10.1038/sj.bjc.6602631
242.
Ito K, et al. RUNX3 attenuates beta-catenin/T cell factors in intestinal tumorigenesis. Cancer Cell. 2008;14:226-237.
Not in our library10.1016/j.ccr.2008.08.004
243.
Sun J, et al. RUNX3 inhibits glioma survival and invasion via suppression of the β-catenin/TCF-4 signaling pathway. J. Neurooncol. 2018;140:15-26.
Not in our library10.1007/s11060-018-2927-0
244.
Saegusa, M., Hashimura, M., & Kuwata, T. Sox4 functions as a positive regulator of β-catenin signaling through upregulation of TCF4 during morular differentiation of endometrial carcinomas. Lab. Invest.92, 511–521 (2012).
Not in our library10.1038/labinvest.2011.196
245.
Sinner D, et al. Sox17 and Sox4 differentially regulate beta-catenin/T-cell factor activity and proliferation of colon carcinoma cells. Mol. Cell. Biol. 2007;27:7802-7815.
Not in our library10.1128/mcb.02179-06
246.
Firestein R, et al. CDK8 is a colorectal cancer oncogene that regulates beta-catenin activity. Nature. 2008;455:547-551.
Not in our library10.1038/nature07179
247.
Gu, X. et al. TCTP promotes glioma cell proliferation in vitro and in vivo via enhanced β-catenin/TCF-4 transcription. Neuro Oncol.16, 217–227 (2014).
Not in our library10.1093/neuonc/not194
248.
Fu CA, et al. TNIK, a novel member of the germinal center kinase family that activates the c-Jun N-terminal kinase pathway and regulates the cytoskeleton. J. Biol. Chem. 1999;274:30729-30737.
Not in our library10.1074/jbc.274.43.30729
249.
Taira K, et al. The Traf2- and Nck-interacting kinase as a putative effector of Rap2 to regulate actin cytoskeleton. J. Biol. Chem. 2004;279:49488-49496.
Not in our library10.1074/jbc.m406370200
250.
Mahmoudi T, et al. The kinase TNIK is an essential activator of Wnt target genes. EMBO J. 2009;28:3329-3340.
Not in our library10.1038/emboj.2009.285
251.
Shitashige M, et al. Traf2- and Nck-interacting kinase is essential for Wnt signaling and colorectal cancer growth. Cancer Res. 2010;70:5024-5033.
Not in our library10.1158/0008-5472.can-10-0306
252.
Sawa M, Masuda M, Yamada T. Targeting the Wnt signaling pathway in colorectal cancer. Expert Opin. Ther. Targets. 2016;20:419-429.
Not in our library10.1517/14728222.2016.1098619
253.
Takahashi, H. et al. Prognostic significance of Traf2- and Nck- interacting kinase (TNIK) in colorectal cancer. BMC Cancer15, 794 (2015).
Not in our library10.1186/s12885-015-1783-y
254.
Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487:330-337.
Not in our library10.1038/nature11252
255.
Collu, G., Hidalgo-Sastre, A. & Brennan, K. Wnt-Notch signalling crosstalk in development and disease. Cell. Mol. Life Sci.71, 3553–3567 (2014).
Not in our library10.1007/s00018-014-1644-x
256.
Couso JP, Arias Martinez. A. Notch is required for wingless signaling in the epidermis of Drosophila. Cell. 1994;79:259-272.
Not in our library10.1016/0092-8674(94)90195-3
257.
Hayward P, et al. Notch modulates Wnt signalling by associating with Armadillo/ß-catenin and regulating its transcriptional activity. Dev. Camb. Engl. 2005;132:1819.
Not in our library10.1242/dev.01724
258.
Camps J, et al. Genetic amplification of the NOTCH modulator LNX2 upregulates the WNT/β-catenin pathway in colorectal cancer. Cancer Res. 2013;73:2003-2013.
Not in our library10.1158/0008-5472.can-12-3159
259.
Borggrefe T, et al. The Notch intracellular domain integrates signals from Wnt, Hedgehog, TGFβ/BMP and hypoxia pathways. Biochim. Biophys. Acta. 2016;1863:303-313.
Not in our library10.1016/j.bbamcr.2015.11.020
260.
Notch and Wnt/β-catenin signaling pathway play important roles in activating liver cancer stem cells · 2015
No notice
261.
Peignon G, et al. Complex interplay between β-catenin signalling and Notch effectors in intestinal tumorigenesis. Gut. 2011;60:166-176.
Not in our library10.1136/gut.2009.204719
262.
Saha, S. K., Yin, Y., Chae, H. S. & Cho, S.-G. Opposing regulation of cancer properties via KRT19-mediated differential modulation of Wnt/β-catenin/Notch signaling in breast and colon cancers. Cancers11, 99 (2019).
Not in our library10.3390/cancers11010099
263.
Gowrikumar S, et al. Correction: Upregulated claudin-1 expression promotes colitis-associated cancer by promoting β-catenin phosphorylation and activation in Notch/p-AKT-dependent manner. Oncogene. 2019;38:6566.
Not in our library10.1038/s41388-019-0864-9
264.
Bangs, F. & Anderson, K. V. Primary cilia and mammalian hedgehog signaling. Cold Spring Harb. Perspect. Biol. 9, a028175 (2017).
Not in our library10.1101/cshperspect.a028175
265.
Rohatgi R, Milenkovic L, Corcoran RB, Scott MP. Hedgehog signal transduction by Smoothened: pharmacologic evidence for a 2-step activation process. Proc. Natl Acad. Sci. USA. 2009;106:3196-3201.
Not in our library10.1073/pnas.0813373106
266.
Jacob J, Briscoe J. Gli proteins and the control of spinal-cord patterning. EMBO Rep. 2003;4:761-765.
Not in our library10.1038/sj.embor.embor896
267.
Wang B, Li Y. Evidence for the direct involvement of {beta}TrCP in Gli3 protein processing. Proc. Natl Acad. Sci. USA. 2006;103:33-38.
Not in our library10.1073/pnas.0509927103
268.
Shin K, et al. Hedgehog/Wnt feedback supports regenerative proliferation of epithelial stem cells in bladder. Nature. 2011;472:110-114.
Not in our library10.1038/nature09851
269.
Farahmand, L., Darvishi, B., Majidzadeh-A, K. & Madjid Ansari, A. Naturally occurring compounds acting as potent anti-metastatic agents and their suppressing effects on Hedgehog and WNT/β-catenin signalling pathways. Cell Prolif. 50, (2017).
Not in our library10.1111/cpr.12299
270.
Qualtrough D, Rees P, Speight B, Williams AC, Paraskeva C. The Hedgehog inhibitor cyclopamine reduces β-catenin-Tcf transcriptional activity, induces E-cadherin expression, and reduces invasion in colorectal cancer cells. Cancers. 2015;7:1885-1899.
Not in our library10.3390/cancers7030867
271.
Harding J, Burtness B. Cetuximab: an epidermal growth factor receptor chemeric human-murine monoclonal antibody. Drugs Today Barc. Spain. 2005;1998:41.
Not in our library10.1358/dot.2005.41.2.882662
272.
Iannello, A. & Ahmad, A. Role of antibody-dependent cell-mediated cytotoxicity in the efficacy of therapeutic anti-cancer monoclonal antibodies. Cancer Metastasis Rev. 24, 487–499 (2005).
Not in our library10.1007/s10555-005-6192-2
273.
Gorter, A. & Meri, S. Immune evasion of tumor cells using membrane-bound complement regulatory proteins. Immunol. Today20, 576–582 (1999).
Not in our library10.1016/s0167-5699(99)01537-6
274.
Imai K, Takaoka A. Comparing antibody and small-molecule therapies for cancer. Nat. Rev. Cancer. 2006;6:714-727.
Not in our library10.1038/nrc1913
275.
Li HK, et al. α-particle therapy for synovial sarcoma in the mouse using an astatine-211-labeled antibody against frizzled homolog 10. Cancer Sci. 2018;109:2302-2309.
Not in our library10.1111/cas.13636
276.
Huang S, Armstrong EA, Benavente S, Chinnaiyan P, Harari PM. Dual-agent molecular targeting of the epidermal growth factor receptor (EGFR): combining anti-EGFR antibody with tyrosine kinase inhibitor. Cancer Res. 2004;64:5355-5362.
Not in our library10.1158/0008-5472.can-04-0562
277.
Gentilucci L, Tolomelli A, Squassabia F. Peptides and peptidomimetics in medicine, surgery and biotechnology. Curr. Med. Chem. 2006;13:2449-2466.
Not in our library10.2174/092986706777935041
278.
Zhong Z, et al. PORCN inhibition synergizes with PI3K/mTOR inhibition in Wnt-addicted cancers. Oncogene. 2019;38:6662-6677.
Not in our library10.1038/s41388-019-0908-1
279.
Teneggi, V. et al. 152O A phase 1, first-in-human dose escalation study of ETC-159 in advanced or metastatic solid tumours. Ann. Oncol. 27, 10.1093/annonc/mdw579.004 (2016).
Not in our library
280.
Madan B, et al. Bone loss from Wnt inhibition mitigated by concurrent alendronate therapy. Bone Res. 2018;6:17.
Not in our library10.1038/s41413-018-0017-8
281.
Funck-Brentano T, et al. Porcupine inhibitors impair trabecular and cortical bone mass and strength in mice. J. Endocrinol. 2018;238:13-23.
Not in our library10.1530/joe-18-0153
282.
Liu J, et al. Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974. Proc. Natl Acad. Sci. USA. 2013;110:20224-20229.
Not in our library10.1073/pnas.1314239110
283.
Madan B, et al. Wnt addiction of genetically defined cancers reversed by PORCN inhibition. Oncogene. 2016;35:2197-2207.
Not in our library10.1038/onc.2015.280
284.
Koo B-K, van Es JH, van den Born M, Clevers H. Porcupine inhibitor suppresses paracrine Wnt-driven growth of Rnf43;Znrf3-mutant neoplasia. Proc. Natl Acad. Sci. USA. 2015;112:7548-7550.
Not in our library10.1073/pnas.1508113112
285.
University of Michigan Rogel Cancer Center. An open label, non-randomized phase ii trial evaluating WNT974 in patients with metastatic head and neck squamous cell carcinoma. NCT02649530, UMCC 2015.157.
Not in our library
286.
Jin, X.-F., Spoettl, G., Maurer, J., Nölting, S. & Auernhammer, C. J. Inhibition of Wnt/β-catenin signaling in neuroendocrine tumors in vitro: antitumoral effects. Cancers12, 345 (2020).
Not in our library10.3390/cancers12020345
287.
Doo DW, et al. Inhibition of the Wnt/β-catenin pathway enhances antitumor immunity in ovarian cancer. Ther. Adv. Med. Oncol. 2020;12:1758835920913798.
Not in our library10.1177/1758835920913798
288.
Array BioPharma. A phase Ib/II multi-center, open label, dose escalation study of WNT974, LGX818 and cetuximab in patients with BRAFV600-mutant KRAS wild-type metastatic colorectal cancer harboring wnt pathway mutations. NCT02278133, CWNT974X2102C.
Not in our library
289.
Novartis Pharmaceuticals. A phase I, open-label, dose escalation study of oral LGK974 in patients with malignancies dependent on Wnt ligands. NCT01351103, CLGK974X2101.
Not in our library
290.
EDDC, A. R. E. & PPD. A phase 1A/B study to evaluate the safety and tolerability of ETC-1922159 in advanced solid tumours. NCT02521844, D3-002.
Not in our library
291.
Li C, et al. Identification of RSPO2 Fusion Mutations and Target Therapy Using a Porcupine Inhibitor. Sci. Rep. 2018;8:14244.
Not in our library10.1038/s41598-018-32652-3
292.
Wall JA, et al. Manipulating the Wnt/β-catenin signaling pathway to promote anti-tumor immune infiltration into the TME to sensitize ovarian cancer to ICB therapy. Gynecol. Oncol. 2021;160:285-294.
Not in our library10.1016/j.ygyno.2020.10.031
293.
Li C, et al. The delivery of a Wnt pathway inhibitor toward CSCs requires stable liposome encapsulation and delayed drug release in tumor tissues. Mol. Ther. 2019;27:1558-1567.
Not in our library10.1016/j.ymthe.2019.06.013
294.
Curegenix Inc. & Merck, S. and D. C. A phase 1 open-label dose escalation and dose expansion study of CGX1321 in subjects with advanced solid tumors and phase 1b study of CGX1321 in combination with pembrolizumab in subjects with advanced gastrointestinal tumors. NCT02675946, CGX1321-101.
Not in our library
295.
Proffitt KD, et al. Pharmacological inhibition of the Wnt acyltransferase PORCN prevents growth of WNT-driven mammary cancer. Cancer Res. 2013;73:502-507.
Not in our library10.1158/0008-5472.can-12-2258
296.
Cheng Y, et al. Wnt-C59 arrests stemness and suppresses growth of nasopharyngeal carcinoma in mice by inhibiting the Wnt pathway in the tumor microenvironment. Oncotarget. 2015;6:14428-14439.
Not in our library10.18632/oncotarget.3982
297.
Wang B, et al. Reversion of trichostatin A resistance via inhibition of the Wnt signaling pathway in human pancreatic cancer cells. Oncol. Rep. 2014;32:2015-2022.
Not in our library10.3892/or.2014.3476
298.
Cheng D, et al. Discovery of pyridinyl acetamide derivatives as potent, selective, and orally bioavailable porcupine inhibitors. ACS Med. Chem. Lett. 2016;7:676-680.
Not in our library10.1021/acsmedchemlett.6b00038
299.
Chen B, et al. Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer. Nat. Chem. Biol. 2009;5:100-107.
Not in our library10.1038/nchembio.137
300.
Wang X, et al. The development of highly potent inhibitors for porcupine. J. Med. Chem. 2013;56:2700-2704.
Not in our library10.1021/jm400159c
301.
Kleszcz R, Szymańska A, Krajka-Kuźniak V, Baer-Dubowska W, Paluszczak J. Inhibition of CBP/β-catenin and porcupine attenuates Wnt signaling and induces apoptosis in head and neck carcinoma cells. Cell. Oncol. Dordr. 2019;42:505-520.
Not in our library10.1007/s13402-019-00440-4
302.
Liu, C. et al. Newly developed CK1-specific inhibitors show specifically stronger effects on CK1 mutants and colon cancer cell lines. Int. J. Mol. Sci. 20, 6184 (2019).
Not in our library10.3390/ijms20246184
303.
García-Reyes B, et al. Discovery of inhibitor of Wnt production 2 (IWP-2) and related compounds as selective ATP-competitive inhibitors of casein kinase 1 (CK1) δ/ε. J. Med. Chem. 2018;61:4087-4102.
Not in our library10.1021/acs.jmedchem.8b00095
304.
Mo M-L, et al. Inhibition of the Wnt palmitoyltransferase porcupine suppresses cell growth and downregulates the Wnt/β-catenin pathway in gastric cancer. Oncol. Lett. 2013;5:1719-1723.
Not in our library10.3892/ol.2013.1256
305.
Gurney A, et al. Wnt pathway inhibition via the targeting of Frizzled receptors results in decreased growth and tumorigenicity of human tumors. Proc. Natl Acad. Sci. USA. 2012;109:11717-11722.
Not in our library10.1073/pnas.1120068109
306.
Le PN, McDermott JD, Jimeno A. Targeting the Wnt pathway in human cancers: therapeutic targeting with a focus on OMP-54F28. Pharmacol. Ther. 2015;146:1-11.
Not in our library10.1016/j.pharmthera.2014.08.005
307.
Hoey, T. (ed.) Development of FZD8-Fc (OMP-54 F28), aWnt signaling antagonist that inhibits tumor growth and reduces tumor initiating cell frequency. Presented at AACR Annual Meeting; 2013 April; Washington DC (2013).
Not in our library
308.
Fischer MM, et al. WNT antagonists exhibit unique combinatorial antitumor activity with taxanes by potentiating mitotic cell death. Sci. Adv. 2017;3:e1700090.
Not in our library10.1126/sciadv.1700090
309.
Jimeno A, et al. A first-in-human phase I study of the anticancer stem cell agent ipafricept (OMP-54F28), a decoy receptor for Wnt ligands, in patients with advanced solid tumors. Clin. Cancer Res. 2017;23:7490-7497.
Not in our library10.1158/1078-0432.ccr-17-2157
310.
Moore KN, et al. A phase 1b dose escalation study of ipafricept (OMP54F28) in combination with paclitaxel and carboplatin in patients with recurrent platinum-sensitive ovarian cancer. Gynecol. Oncol. 2019;154:294-301.
Not in our library10.1016/j.ygyno.2019.04.001
311.
Davis SL, et al. A phase 1b dose escalation study of Wnt pathway inhibitor vantictumab in combination with nab-paclitaxel and gemcitabine in patients with previously untreated metastatic pancreatic cancer. Invest. N. Drugs. 2020;38:821-830.
Not in our library10.1007/s10637-019-00824-1
312.
Diamond JR, et al. Phase Ib clinical trial of the anti-frizzled antibody vantictumab (OMP-18R5) plus paclitaxel in patients with locally advanced or metastatic HER2-negative breast cancer. Breast Cancer Res. Treat. 2020;184:53-62.
Not in our library10.1007/s10549-020-05817-w
313.
Salik B, et al. Targeting RSPO3-LGR4 signaling for leukemia stem cell eradication in acute myeloid leukemia. Cancer Cell. 2020;38:263-278.e6.
Not in our library10.1016/j.ccell.2020.05.014
314.
Bendell J, et al. Initial results from a phase 1a/b study of OMP-131R10, a first-in-class anti-RSPO3 antibody, in advanced solid tumors and previously treated metastatic colorectal cancer (CRC). Eur. J. Cancer. 2016;69:S29-S30.
Not in our library10.1016/s0959-8049(16)32668-5
315.
Pavlovic Z, et al. A synthetic anti-Frizzled antibody engineered for broadened specificity exhibits enhanced anti-tumor properties. mAbs. 2018;10:1157-1167.
Not in our library10.1080/19420862.2018.1515565
316.
Wall JA, Klempner SJ, Arend RC. The anti-DKK1 antibody DKN-01 as an immunomodulatory combination partner for the treatment of cancer. Expert Opin. Investig. Drugs. 2020;29:639-644.
Not in our library10.1080/13543784.2020.1769065
317.
34th Annual Meeting & Pre-Conference Programs of the Society for Immunotherapy of Cancer (SITC 2019): part 1 · 2019
Not checked
318.
Leap Therapeutics, Inc. A phase 2 study evaluating the efficacy and safety of DKN-01 as a monotherapy or in combination with paclitaxel in patients with recurrent epithelial endometrial, epithelial ovarian cancer, or carcinosarcoma. NCT03395080, DEK-DKK1-P204.
Not in our library
319.
Choi MY, et al. Pre-clinical specificity and safety of UC-961, a first-in-class monoclonal antibody targeting ROR1. Clin. Lymphoma Myeloma Leuk. 2015;15(Suppl):S167-S169.
Not in our library10.1016/j.clml.2015.02.010
320.
Giraudet A-L, et al. A first-in-human study investigating biodistribution, safety and recommended dose of a new radiolabeled MAb targeting FZD10 in metastatic synovial sarcoma patients. BMC Cancer. 2018;18:646.
Not in our library10.1186/s12885-018-4544-x
321.
Säfholm A, et al. The Wnt-5a-derived hexapeptide Foxy-5 inhibits breast cancer metastasis in vivo by targeting cell motility. Clin. Cancer Res. 2008;14:6556-6563.
Not in our library10.1158/1078-0432.ccr-08-0711
322.
Canesin G, et al. Treatment with the WNT5A-mimicking peptide Foxy-5 effectively reduces the metastatic spread of WNT5A-low prostate cancer cells in an orthotopic mouse model. PLoS ONE. 2017;12:e0184418.
Not in our library10.1371/journal.pone.0184418
323.
Pak S, et al. The small molecule WNT/β-catenin inhibitor CWP232291 blocks the growth of castration-resistant prostate cancer by activating the endoplasmic reticulum stress pathway. J. Exp. Clin. Cancer Res. 2019;38:342.
Not in our library10.1186/s13046-019-1342-5
324.
Gunaydin H, Gu Y, Huang X. Novel binding mode of a potent and selective tankyrase inhibitor. PLoS ONE. 2012;7:e33740.
Not in our library10.1371/journal.pone.0033740
325.
Mukai, T., Fujita, S. & Morita, Y. Tankyrase (PARP5) inhibition induces bone loss through accumulation of its substrate SH3BP2. Cells8, 195 (2019).
Not in our library10.3390/cells8020195
326.
Fujita S, et al. Pharmacological inhibition of tankyrase induces bone loss in mice by increasing osteoclastogenesis. Bone. 2018;106:156-166.
Not in our library10.1016/j.bone.2017.10.017
327.
Ueki Y, et al. Mutations in the gene encoding c-Abl-binding protein SH3BP2 cause cherubism. Nat. Genet. 2001;28:125-126.
Not in our library10.1038/88832
328.
Levaot N, et al. 3BP2-deficient mice are osteoporotic with impaired osteoblast and osteoclast functions. J. Clin. Invest. 2011;121:3244-3257.
Not in our library10.1172/jci45843
329.
Tanaka N, et al. APC mutations as a potential biomarker for sensitivity to tankyrase inhibitors in colorectal cancer. Mol. Cancer Ther. 2017;16:752-762.
Not in our library10.1158/1535-7163.mct-16-0578
330.
Shetti, D. et al. Low dose of paclitaxel combined with XAV939 attenuates metastasis, angiogenesis and growth in breast cancer by suppressing Wnt signaling. Cells8, 892 (2019).
Not in our library10.3390/cells8080892
331.
Wang J, et al. Bufalin inhibits gastric cancer invasion and metastasis by down-regulating Wnt/ASCL2 expression. Oncotarget. 2018;9:23320-23333.
Not in our library10.18632/oncotarget.24157
332.
Tian X, et al. XAV939 inhibits the stemness and migration of neuroblastoma cancer stem cells via repression of tankyrase 1. Int. J. Oncol. 2014;45:121-128.
Not in our library10.3892/ijo.2014.2406
333.
Tian X-H, et al. XAV939, a tankyrase 1 inhibitior, promotes cell apoptosis in neuroblastoma cell lines by inhibiting Wnt/β-catenin signaling pathway. J. Exp. Clin. Cancer Res. 2013;32:100.
Not in our library10.1186/1756-9966-32-100
334.
Busch, A. M. et al. In Experimental and Molecular Therapeutics (American Association for Cancer Research, 2012).
Not in our library
335.
Stakheev D, et al. The WNT/β-catenin signaling inhibitor XAV939 enhances the elimination of LNCaP and PC-3 prostate cancer cells by prostate cancer patient lymphocytes in vitro. Sci. Rep. 2019;9:4761.
Not in our library10.1038/s41598-019-41182-5
336.
Waaler J, et al. Novel synthetic antagonists of canonical Wnt signaling inhibit colorectal cancer cell growth. Cancer Res. 2011;71:197-205.
Not in our library10.1158/0008-5472.can-10-1282
337.
Waaler J, et al. A novel tankyrase inhibitor decreases canonical Wnt signaling in colon carcinoma cells and reduces tumor growth in conditional APC mutant mice. Cancer Res. 2012;72:2822-2832.
Not in our library10.1158/0008-5472.can-11-3336
338.
Lau T, et al. A novel tankyrase small-molecule inhibitor suppresses APC mutation-driven colorectal tumor growth. Cancer Res. 2013;73:3132-3144.
Not in our library10.1158/0008-5472.can-12-4562
339.
Solberg NT, et al. TANKYRASE inhibition enhances the antiproliferative effect of PI3K and EGFR inhibition, mutually affecting β-CATENIN and AKT signaling in colorectal cancer. Mol. Cancer Res. MCR. 2018;16:543-553.
Not in our library10.1158/1541-7786.mcr-17-0362
340.
Kierulf-Vieira, K. S. et al. A small-molecule tankyrase inhibitor reduces glioma stem cell proliferation and sphere formation. Cancers12, 1630 (2020).
Not in our library10.3390/cancers12061630
341.
Kulak O, et al. Disruption of Wnt/β-catenin signaling and telomeric shortening are inextricable consequences of tankyrase inhibition in human cells. Mol. Cell. Biol. 2015;35:2425-2435.
Not in our library10.1128/mcb.00392-15
342.
Martins-Neves SR, et al. IWR-1, a tankyrase inhibitor, attenuates Wnt/β-catenin signaling in cancer stem-like cells and inhibits in vivo the growth of a subcutaneous human osteosarcoma xenograft. Cancer Lett. 2018;414:1-15.
Not in our library10.1016/j.canlet.2017.11.004
343.
Lee SC, Kim O-H, Lee SK, Kim S-J. IWR-1 inhibits epithelial-mesenchymal transition of colorectal cancer cells through suppressing Wnt/β-catenin signaling as well as survivin expression. Oncotarget. 2015;6:27146-27159.
Not in our library10.18632/oncotarget.4354
344.
Busch AM, et al. Evidence for tankyrases as antineoplastic targets in lung cancer. BMC Cancer. 2013;13:211.
Not in our library10.1186/1471-2407-13-211
345.
Ma L, et al. Tankyrase inhibitors attenuate WNT/β-catenin signaling and inhibit growth of hepatocellular carcinoma cells. Oncotarget. 2015;6:25390-25401.
Not in our library10.18632/oncotarget.4455
346.
Huang J, Qu Q, Guo Y, Xiang Y, Feng D. Tankyrases/β-catenin signaling pathway as an anti-proliferation and anti-metastatic target in hepatocarcinoma cell lines. J. Cancer. 2020;11:432-440.
Not in our library10.7150/jca.30976
347.
Arqués O, et al. Tankyrase inhibition blocks Wnt/β-catenin pathway and reverts resistance to PI3K and AKT inhibitors in the treatment of colorectal cancer. Clin. Cancer Res. 2016;22:644-656.
Not in our library10.1158/1078-0432.ccr-14-3081
348.
Scarborough HA, et al. AZ1366: an inhibitor of tankyrase and the canonical Wnt pathway that limits the persistence of non–small cell lung cancer cells following EGFR inhibition. Clin. Cancer Res. 2017;23:1531-1541.
Not in our library10.1158/1078-0432.ccr-16-1179
349.
Quackenbush KS, et al. The novel tankyrase inhibitor (AZ1366) enhances irinotecan activity in tumors that exhibit elevated tankyrase and irinotecan resistance. Oncotarget. 2016;7:28273-28285.
Not in our library10.18632/oncotarget.8626
350.
Mizutani A, et al. RK-287107, a potent and specific tankyrase inhibitor, blocks colorectal cancer cell growth in a preclinical model. Cancer Sci. 2018;109:4003-4014.
Not in our library10.1111/cas.13805
351.
Wang S, et al. Small-molecule modulation of Wnt signaling via modulating the Axin-LRP5/6 interaction. Nat. Chem. Biol. 2013;9:579-585.
Not in our library10.1038/nchembio.1309
352.
Liu M, et al. IC261, a specific inhibitor of CK1δ/ε, promotes aerobic glycolysis through p53-dependent mechanisms in colon cancer. Int. J. Biol. Sci. 2020;16:882-892.
Not in our library10.7150/ijbs.40960
353.
Varghese RT, et al. Casein kinase 1 epsilon regulates glioblastoma cell survival. Sci. Rep. 2018;8:13621.
Not in our library10.1038/s41598-018-31864-x
354.
Cheong JK, et al. IC261 induces cell cycle arrest and apoptosis of human cancer cells via CK1δ/ɛ and Wnt/β-catenin independent inhibition of mitotic spindle formation. Oncogene. 2011;30:2558-2569.
Not in our library10.1038/onc.2010.627
355.
Yuan F, et al. IC261 suppresses progression of hepatocellular carcinoma in a casein kinase 1 δ/ε independent manner. Biochem. Biophys. Res. Commun. 2020;523:809-815.
Not in our library10.1016/j.bbrc.2019.12.105
356.
Janovska P, et al. Autocrine signaling by Wnt-5a deregulates chemotaxis of leukemic cells and predicts clinical outcome in chronic lymphocytic leukemia. Clin. Cancer Res. Clin. Cancer Res. 2015;22:459-469.
Not in our library10.1158/1078-0432.ccr-15-0154
357.
Shen, C. et al. The CK1α activator pyrvinium enhances the catalytic efficiency (kcat/ Km) of CK1α. Biochemistry58, 5102–5106 (2019).
Not in our library10.1021/acs.biochem.9b00891
358.
The antihelmintic drug pyrvinium pamoate targets aggressive breast cancer. · 2013
Not checked
359.
Zhang, C., Zhang, Z., Zhang, S., Wang, W. & Hu, P. Targeting of Wnt/β-catenin by anthelmintic drug pyrvinium enhances sensitivity of ovarian cancer cells to chemotherapy. Med. Sci. Monit. 23, 266–275 (2017).
Not in our library10.12659/msm.901667
360.
Smith, T. C., Kinkel, A. W., Gryczko, C. M., & Goulet, J. R. Absorption of pyrvinium pamoate. Clin. Pharmacol. Ther. 19, 802–806 (1976).
Not in our library10.1002/cpt1976196802
361.
Venerando A, Girardi C, Ruzzene M, Pinna LA. Pyrvinium pamoate does not activate protein kinase CK1, but promotes Akt/PKB down-regulation and GSK3 activation. Biochem. J. 2013;452:131-137.
Not in our library10.1042/bj20121140
362.
Takahashi-Yanaga F. Activator or inhibitor? GSK-3 as a new drug target. Biochem. Pharmacol. 2013;86:191-199.
Not in our library10.1016/j.bcp.2013.04.022
363.
Atkinson JM, et al. Activating the Wnt/β-catenin pathway for the treatment of melanoma-application of LY2090314, a novel selective inhibitor of glycogen synthase kinase-3. PLoS ONE. 2015;10:e0125028.
Not in our library10.1371/journal.pone.0125028
364.
Nakata D, et al. Glycogen synthase kinase-3 inhibitors suppress the AR-V7-mediated transcription and selectively inhibit cell growth in AR-V7-positive prostate cancer cells. Prostate. 2017;77:955-961.
Not in our library10.1002/pros.23351
365.
Kunnimalaiyaan S, Schwartz VK, Jackson IA, Clark Gamblin T, Kunnimalaiyaan M. Antiproliferative and apoptotic effect of LY2090314, a GSK-3 inhibitor, in neuroblastoma in vitro. BMC Cancer. 2018;18:560.
Not in our library10.1186/s12885-018-4474-7
366.
Gray JE, et al. A first-in-human phase I dose-escalation, pharmacokinetic, and pharmacodynamic evaluation of intravenous LY2090314, a glycogen synthase kinase 3 inhibitor, administered in combination with pemetrexed and carboplatin. Invest. N. Drugs. 2015;33:1187-1196.
Not in our library10.1007/s10637-015-0278-7
367.
Zhang, C. et al. Overexpression of dishevelled 2 is involved in tumor metastasis and is associated with poor prognosis in hepatocellular carcinoma. Clin. Transl. Oncol. 19, 1507–1517 (2017).
Not in our library10.1007/s12094-017-1697-z
368.
Wei Q, et al. Dishevelled family proteins are expressed in non-small cell lung cancer and function differentially on tumor progression. Lung Cancer Amst. Neth. 2008;62:181-192.
Not in our library10.1016/j.lungcan.2008.06.018
369.
Khan, A. S. et al. Dishevelled proteins are significantly upregulated in chronic lymphocytic leukaemia. Tumour Biol. 37, 11947–11957 (2016).
Not in our library10.1007/s13277-016-5039-5
370.
Fujii N, et al. An antagonist of dishevelled protein-protein interaction suppresses beta-catenin-dependent tumor cell growth. Cancer Res. 2007;67:573-579.
Not in our library10.1158/0008-5472.can-06-2726
371.
Grandy D, et al. Discovery and characterization of a small molecule inhibitor of the PDZ domain of dishevelled. J. Biol. Chem. 2009;284:16256-16263.
Not in our library10.1074/jbc.m109.009647
372.
Jamieson C, Sharma M, Henderson BR. Targeting the β-catenin nuclear transport pathway in cancer. Semin. Cancer Biol. 2014;27:20-29.
Not in our library10.1016/j.semcancer.2014.04.012
373.
Masuda M, Sawa M, Yamada T. Therapeutic targets in the Wnt signaling pathway: Feasibility of targeting TNIK in colorectal cancer. Pharmacol. Ther. 2015;156:1-9.
Not in our library10.1016/j.pharmthera.2015.10.009
374.
Lee, Y., Jung, J. I., Park, K. Y., Kim, S. A. & Kim, J. Synergistic inhibition effect of TNIK inhibitor KY-05009 and receptor tyrosine kinase inhibitor dovitinib on IL-6-induced proliferation and Wnt signaling pathway in human multiple myeloma cells. Oncotarget8, 41091–41101 (2017).
Not in our library10.18632/oncotarget.17056
375.
Yamada T, Masuda M. Emergence of TNIK inhibitors in cancer therapeutics. Cancer Sci. 2017;108:818-823.
Not in our library10.1111/cas.13203
376.
TNIK inhibition abrogates colorectal cancer stemness · 2016
No notice
377.
Sugano T, et al. Pharmacological blockage of transforming growth factor-β signalling by a Traf2- and Nck-interacting kinase inhibitor, NCB-0846. Br. J. Cancer. 2021;124:228-236.
Not in our library10.1038/s41416-020-01162-3
378.
Sekita, T. et al. Feasibility of targeting Traf2-and-Nck-interacting kinase in synovial sarcoma. Cancers12, 1258 (2020).
Not in our library10.3390/cancers12051258
379.
Characterization of the ERG-regulated Kinome in Prostate Cancer Identifies TNIK as a Potential Therapeutic Target · 2019
Not checked
380.
Kim JY, Park G, Krishnan M, Ha E, Chun K-S. Selective Wnt/β-catenin small-molecule inhibitor CWP232228 impairs tumor growth of colon cancer. Anticancer Res. 2019;39:3661-3667.
Not in our library10.21873/anticanres.13514
381.
Kim J-Y, et al. CWP232228 targets liver cancer stem cells through Wnt/β-catenin signaling: a novel therapeutic approach for liver cancer treatment. Oncotarget. 2016;7:20395-20409.
Not in our library10.18632/oncotarget.7954
382.
Jang G-B, et al. Wnt/β-catenin small-molecule inhibitor CWP232228 preferentially inhibits the growth of breast cancer stem-like cells. Cancer Res. 2015;75:1691-1702.
Not in our library10.1158/0008-5472.can-14-2041
383.
Fang, L. et al. A small-molecule antagonist of the β-catenin/TCF4 interaction blocks the self-renewal of cancer stem cells and suppresses tumorigenesis. Cancer Res. 76, 891–901 (2016).
Not in our library10.1158/0008-5472.can-15-1519
384.
Fiskus W, et al. Abstract C144: Treatment with β-catenin antagonist BC2059 exhibits single agent efficacy and exerts superior activity with tyrosine kinase inhibitor (TKI) or histone deacetylase (HDAC) inhibitor against human AML, CML, and myeloproliferative neoplasm (MPN) progenitor cells. Mol. Cancer Ther. 2011;10:C144-C144.
Not in our library10.1186/1476-4598-10-144
385.
Fiskus W, et al. Pre-clinical efficacy of combined therapy with novel β-catenin antagonist BC2059 and histone deacetylase inhibitor against AML cells. Leukemia. 2015;29:1267-1278.
Not in our library10.1038/leu.2014.340
386.
Small Molecule Inhibitors of Wnt/β-Catenin/Lef-1 Signaling Induces Apoptosis in Chronic Lymphocytic Leukemia Cells In Vitro and In Vivo · 2010
Not checked
387.
Minke KS, et al. Small molecule inhibitors of WNT signaling effectively induce apoptosis in acute myeloid leukemia cells. Eur. J. Haematol. 2009;82:165-175.
Not in our library10.1111/j.1600-0609.2008.01188.x
388.
Wei W, Chua M-S, Grepper S, So S. Small molecule antagonists of Tcf4/beta-catenin complex inhibit the growth of HCC cells in vitro and in vivo. Int. J. Cancer. 2010;126:2426-2436.
Not in our library10.1002/ijc.24810
389.
Zhang M, Wang Z, Zhang Y, Guo W, Ji H. Structure-based optimization of small-molecule inhibitors for the β-catenin/b-cell lymphoma 9 protein–protein interaction. J. Med. Chem. 2018;61:2989-3007.
Not in our library10.1021/acs.jmedchem.8b00068
390.
Gabata R, et al. Anti-tumor activity of the small molecule inhibitor PRI-724 against β-catenin-activated hepatocellular carcinoma. Anticancer Res. 2020;40:5211-5219.
Not in our library10.21873/anticanres.14524
391.
Hirakawa T, et al. β-catenin signaling inhibitors ICG-001 and C-82 improve fibrosis in preclinical models of endometriosis. Sci. Rep. 2019;9:20056.
Not in our library10.1038/s41598-019-56302-4
392.
Safety, Tolerability, and Preliminary Efficacy of the Anti-Fibrotic Small Molecule PRI-724, a CBP/β-Catenin Inhibitor, in Patients with Hepatitis C Virus-related Cirrhosis: A Single-Center, Open-Label, Dose Escalation Phase 1 Trial · 2017
Not checked
393.
Mani, M. et al. BCL9 promotes tumor progression by conferring enhanced proliferative, metastatic, and angiogenic properties to cancer cells. Cancer Res. 69, 7577–7586 (2009).
Not in our library10.1158/0008-5472.can-09-0773
394.
Deka J, et al. Bcl9/Bcl9l are critical for Wnt-mediated regulation of stem cell traits in colon epithelium and adenocarcinomas. Cancer Res. 2010;70:6619-6628.
Not in our library10.1158/0008-5472.can-10-0148
395.
Takada, K. et al. Targeted disruption of the BCL9/β-catenin complex inhibits oncogenic Wnt signaling. Sci. Transl. Med. 4, 148ra117 (2012).
Not in our library10.1126/scitranslmed.3003808
396.
Ashrafizadeh M, Ahmadi Z, Farkhondeh T, Samarghandian S. Resveratrol targeting the Wnt signaling pathway: A focus on therapeutic activities. J. Cell. Physiol. 2020;235:4135-4145.
Not in our library10.1002/jcp.29327
397.
Flaig, T. W. et al. A phase I and pharmacokinetic study of silybin-phytosome in prostate cancer patients. Invest. New Drugs25, 139–146 (2007).
Not in our library10.1007/s10637-006-9019-2
398.
Lu W, Lin C, Li Y. Rottlerin induces Wnt co-receptor LRP6 degradation and suppresses both Wnt/β-catenin and mTORC1 signaling in prostate and breast cancer cells. Cell. Signal. 2014;26:1303-1309.
Not in our library10.1016/j.cellsig.2014.02.018
399.
Lai C-S, et al. Tetrahydrocurcumin is more effective than curcumin in preventing azoxymethane-induced colon carcinogenesis. Mol. Nutr. Food Res. 2011;55:1819-1828.
Not in our library10.1002/mnfr.201100290
400.
Nguyen AV, et al. Results of a phase I pilot clinical trial examining the effect of plant-derived resveratrol and grape powder on Wnt pathway target gene expression in colonic mucosa and colon cancer. Cancer Manag. Res. 2009;1:25-37.
Not in our library10.2147/cmar.s4544
401.
University of California, I. & Gateway for Cancer Research. Phase I Biomarker Study of Dietary Grape-derived Low Dose Resveratrol for Colon Cancer Prevention. NCT00578396, OCRT07046.
Not in our library
402.
Villota, H., Röthlisberger, S. & Pedroza-Díaz, J. Modulation of the canonical Wnt signaling pathway by dietary polyphenols, an opportunity for colorectal cancer chemoprevention and treatment. Nutr. Cancer 1–20, 10.1080/01635581.2021.1884730 (2021).
Not in our library10.1080/01635581.2021.1884730
403.
Sangeetha N, et al. Oral supplementation of silibinin prevents colon carcinogenesis in a long term preclinical model. Eur. J. Pharmacol. 2010;643:93-100.
Not in our library10.1016/j.ejphar.2010.05.060
404.
Chen M, et al. The anti-helminthic niclosamide inhibits Wnt/Frizzled1 signaling. Biochemistry. 2009;48:10267-10274.
Not in our library10.1021/bi9009677
405.
Egashira I, et al. Celecoxib and 2,5‐dimethylcelecoxib inhibit intestinal cancer growth by suppressing the Wnt/β‐catenin signaling pathway. Cancer Sci. 2016;108:108-115.
Not in our library10.1111/cas.13106
406.
Lu W, Li Y. Salinomycin suppresses LRP6 expression and inhibits both Wnt/β-catenin and mTORC1 signaling in breast and prostate cancer cells. J. Cell. Biochem. 2014;115:1799-1807.
Not in our library10.1002/jcb.24850
407.
Li L, Mao J, Sun L, Liu W, Wu D. Second cysteine-rich domain of Dickkopf-2 activates canonical Wnt signaling pathway via LRP-6 independently of dishevelled. J. Biol. Chem. 2002;277:5977-5981.
Not in our library10.1074/jbc.m111131200
408.
Ahn VE, et al. Structural basis of Wnt signaling inhibition by Dickkopf binding to LRP5/6. Dev. Cell. 2011;21:862-873.
Not in our library10.1016/j.devcel.2011.09.003
409.
Bu Q, et al. The crystal structure of full-length Sizzled from Xenopus laevis yields insights into Wnt-antagonistic function of secreted Frizzled-related proteins. J. Biol. Chem. 2017;292:16055-16069.
Not in our library10.1074/jbc.m117.791756
410.
Bhat RA, Stauffer B, Komm BS, Bodine PVN. Structure-function analysis of secreted frizzled-related protein-1 for its Wnt antagonist function. J. Cell. Biochem. 2007;102:1519-1528.
Not in our library10.1002/jcb.21372
411.
Kerekes K, Bányai L, Patthy L. Wnts grasp the WIF domain of Wnt Inhibitory Factor 1 at two distinct binding sites. FEBS Lett. 2015;589:3044-3051.
Not in our library10.1016/j.febslet.2015.08.031
412.
Semënov, M., Tamai, K. & He, X. SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor. J. Biol. Chem. 280, 26770–26775 (2005).
Not in our library10.1074/jbc.m504308200
413.
Piccolo S, et al. The head inducer Cerberus is a multifunctional antagonist of Nodal, BMP and Wnt signals. Nature. 1999;397:707-710.
Not in our library10.1038/17820
414.
Ahn Y, Sims C, Logue JM, Weatherbee SD, Krumlauf R. Lrp4 and Wise interplay controls the formation and patterning of mammary and other skin appendage placodes by modulating Wnt signaling. Development. 2013;140:583-593.
Not in our library10.1242/dev.085118
415.
Zhu W, et al. IGFBP-4 is an inhibitor of canonical Wnt signalling required for cardiogenesis. Nature. 2008;454:345-349.
Not in our library10.1038/nature07027
416.
Kakugawa S, et al. Notum deacylates Wnt proteins to suppress signalling activity. Nature. 2015;519:187-192.
Not in our library10.1038/nature14259
417.
Zhang X, et al. Tiki1 is required for head formation via Wnt cleavage-oxidation and inactivation. Cell. 2012;149:1565-1577.
Not in our library10.1016/j.cell.2012.04.039
418.
OncoMed Pharmaceuticals, Inc. A phase 1 dose escalation study of OMP-18R5 in subjects with solid tumors. NCT01345201, 18R5-001.
Not in our library
419.
OncoMed Pharmaceuticals, Inc. A phase 1b dose escalation study of vantictumab (OMP-18R5) in combination with paclitaxel in patients with locally recurrent or metastatic breast cancer. NCT01973309, 18R5-002.
Not in our library
420.
OncoMed Pharmaceuticals, Inc. A phase 1b dose escalation study of vantictumab (OMP-18R5) in combination with nab-paclitaxel and gemcitabine in patients with previously untreated stage IV pancreatic cancer. NCT02005315, 18R5-003R5.
Not in our library10.1007/s10637-019-00824-1
421.
OncoMed Pharmaceuticals, Inc. & Bayer. A phase 1 dose escalation study of OMP-54F28 in subjects with solid tumors. NCT01608867, 54F28-001F28.
Not in our library
422.
OncoMed Pharmaceuticals, Inc. A phase 1b dose escalation study of OMP-54F28 in combination with sorafenib in patients with hepatocellular cancer. NCT02069145, 54F28-004.
Not in our library
423.
OncoMed Pharmaceuticals, Inc. A phase 1b dose escalation study of OMP-54F28 in combination with paclitaxel and carboplatin in patients with recurrent platinum-sensitive ovarian cancer. NCT02092363, 54F28-003.
Not in our library10.1016/j.ygyno.2019.04.001
424.
OncoMed Pharmaceuticals, Inc. A phase 1b dose escalation study of omp-54f28 in combination with nab-paclitaxel and gemcitabine in patients with previously untreated stage IV pancreatic cancer. NCT02050178, 54F28-002.
Not in our library
425.
WntResearch AB. Phase I dose escalating study to evaluate the safety, tolerability, anti-tumour activity and pharmacokinetic and pharmacodynamic profiles of foxy-5 in patients with metastatic breast, colon or prostate cancer. NCT02020291, SMR-2562.
Not in our library
426.
WntResearch AB. Phase Ib dose escalating study to evaluate the safety, tolerability and pharmacodynamic response of foxy-5 in patients with metastatic breast-, colon- or prostate cancer. NCT02655952, SMR-3164.
Not in our library
427.
WntResearch A. B. et al. A randomized, multicentre, open-label controlled phase II trial of foxy-5 as neo-adjuvant therapy in subjects with Wnt-5a low colon cancer. NCT03883802, SMS-0472B.
Not in our library
428.
Leap Therapeutics, Inc. A Pilot Study of DKN-01 and Lenalidomide (Revlimid®)/Dexamethasone Versus Lenalidomide/Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma. https://clinicaltrials.gov/ct2/show/NCT01711671 (2017).
Not in our library
429.
Leap Therapeutics, Inc. A Two Part Phase 1 Multicenter Open-label Study of DKN-01 Given Intravenously. Part A: Dose-Escalation in Patients with Multiple Myeloma or Advanced Solid Tumors. Part B: Expansion Cohort in Patients With Relapsed/Refractory Non-Small Cell Lung Cancer (NSCLC). https://clinicaltrials.gov/ct2/show/NCT01457417 (2016).
Not in our library
430.
Goyal L, et al. Phase I and biomarker study of the Wnt pathway modulator DKN-01 in combination with gemcitabine/cisplatin in advanced biliary tract cancer. Clin. Cancer Am. 2020;26:6158-6167.
Not in our library10.1158/1078-0432.ccr-20-1310
431.
Lipika, G. A Single Arm Phase II Study of the Combination of DKN-01 and Nivolumab in Previously Treated Patients With Advanced Biliary Tract Cancer (BTC). https://clinicaltrials.gov/ct2/show/NCT04057365 (2021).
Not in our library
432.
Marquardt, D. J. U. A Phase I/II Multicenter, Open-label Study of DKN-01 to Investigate the Anti-tumor Activity and Safety of DKN-01 in Patients With Hepatocellular Carcinoma and WNT Signaling Alterations. https://clinicaltrials.gov/ct2/show/NCT03645980 (2020).
Not in our library
433.
Thomas Kipps. A Phase I clinical trial to determine the safety and tolerability of UC-961 (Cirmtuzumab), an anti-ROR1 monoclonal antibody, for the treatment of patients with relapsed or refractory chronic lymphocytic leukemia who are ineligible for chemotherapy. NCT02222688, #140141.
Not in our library
434.
University of California, S. D., California Institute for Regenerative Medicine & Oncternal Therapeutics, I. A phase 1b/2 study of the ROR1-targeting monoclonal antibody, Cirmtuzumab (UC-961), and the bruton tyrosine kinase inhibitor, ibrutinib, in patients with B-cell lymphoid malignancies. NCT03088878, 170127.
Not in our library
435.
MD, B. P. A Phase 1b Pilot Clinical Trial of Cirmtuzumab, an Anti-ROR1 Monoclonal Antibody, in Combination With Paclitaxel for the Treatment of Patients With Metastatic, or Locally Advanced, Unresectable Breast Cancer. https://clinicaltrials.gov/ct2/show/NCT02776917 (2021).
Not in our library
436.
Choi MY, et al. Phase I Trial: Cirmtuzumab Inhibits ROR1 Signaling and Stemness Signatures in Patients with Chronic Lymphocytic Leukemia. Cell Stem Cell. 2018;22:951-959.e3.
Not in our library10.1016/j.stem.2018.05.018
437.
H. Lee Moffitt Cancer Center and Research Institute. A Phase 2 Study to Assess the Efficacy, Safety, Pharmacokinetic and Pharmacodynamic Parameters of Umbralisib in Treatment Naïve Patients With Chronic Lymphocytic Leukemia (CLL). https://clinicaltrials.gov/ct2/show/NCT04163718 (2021).
Not in our library
438.
University of Washington. A Phase II Trial of Umbralisib and Pembrolizumab in Patients With Relapsed or Refractory Classical Hodgkin Lymphoma. https://clinicaltrials.gov/ct2/show/NCT03776864 (2021).
Not in our library
439.
Mehta, A. Phase Ib/II Trial of Ublituximab and Umbralisib With CHOP (U2-CHOP) Followed by U2 Maintenance (U2-CHOP-U2) in Previously Untreated Mantle Cell Lymphoma (MCL). https://clinicaltrials.gov/ct2/show/NCT04692155 (2021).
Not in our library
440.
Eli Lilly and Company. A Phase 2 Study of LY2090314 in Participants With Acute Leukemia. https://clinicaltrials.gov/ct2/show/NCT01214603 (2018).
Not in our library
441.
Eli Lilly and Company. Phase 1 Dose Escalation Study of LY2090314 in Patients With Advanced or Metastatic Cancer in Combination With Pemetrexed and Carboplatin. https://clinicaltrials.gov/ct2/show/NCT01287520 (2018).
Not in our library
442.
Rizzieri DA, et al. An open-label phase 2 study of glycogen synthase kinase-3 inhibitor LY2090314 in patients with acute leukemia. Leuk. Lymphoma. 2016;57:1800-1806.
Not in our library10.3109/10428194.2015.1122781
443.
Prism Pharma Co., Ltd. A Phase Ia/Ib Clinical Trial of PRI-724 in Patients With Advanced Solid Tumors. https://clinicaltrials.gov/ct2/show/NCT01302405 (2017).
Not in our library
444.
Prism Pharma Co., Ltd. Phase Ib Multicenter, Cohort Dose Escalation Trial to Determine the Safety, Tolerance and Preliminary Antineoplastic Activity of Gemcitabine Administered in Combination With Continuous Intravenous Doses of PRI-724, a CBP/ β- Catenin Inhibitor, to Patients With Advanced or Metastatic Pancreatic Adenocarcinoma Eligible for Second-Line Therapy After Failing First-Line Therapy With FOLFIRINOX (or FOLFOX). https://clinicaltrials.gov/ct2/show/NCT01764477 (2017).
Not in our library
445.
University of Southern California. PRIMIER*: Randomized Phase II Trial of mFOLFOX6/Bevacizumab With or Without PRI-724 as First Line Treatment for Metastatic Colorectal Cancer. https://clinicaltrials.gov/ct2/show/NCT02413853 (2017).
Not in our library
446.
Iterion Therapeutics. Phase 1 Trial of BC2059 (Tegavivint) in Patients With Unresectable Desmoid Tumor. https://clinicaltrials.gov/ct2/show/NCT03459469 (2021).
Not in our library
447.
Jeong JB, Lee J, Lee S-H. TCF4 is a molecular target of resveratrol in the prevention of colorectal cancer. Int. J. Mol. Sci. 2015;16:10411-10425.
Not in our library10.3390/ijms160510411
448.
Cilibrasi C, et al. Resveratrol impairs glioma stem cells proliferation and motility by modulating the Wnt signaling pathway. PLoS ONE. 2017;12:e0169854.
Not in our library10.1371/journal.pone.0169854
449.
Liu Z-L, et al. Inactivated Wnt signaling in resveratrol-treated epidermal squamous cancer cells and its biological implication. Oncol. Lett. 2017;14:2239-2243.
Not in our library10.3892/ol.2017.6458
450.
Mojsin M, Vicentic JM, Schwirtlich M, Topalovic V, Stevanovic M. Quercetin reduces pluripotency, migration and adhesion of human teratocarcinoma cell line NT2/D1 by inhibiting Wnt/β-catenin signaling. Food Funct. 2014;5:2564-2573.
Not in our library10.1039/c4fo00484a
451.
Baruah MM, Khandwekar AP, Sharma N. Quercetin modulates Wnt signaling components in prostate cancer cell line by inhibiting cell viability, migration, and metastases. Tumour Biol. 2016;37:14025-14034.
Not in our library10.1007/s13277-016-5277-6
452.
Shan B-E, Wang M-X, Li R. Quercetin inhibit human SW480 colon cancer growth in association with inhibition of cyclin D1 and survivin expression through Wnt/beta-catenin signaling pathway. Cancer Invest. 2009;27:604-612.
Not in our library10.1080/07357900802337191
453.
Amado NG, et al. Isoquercitrin suppresses colon cancer cell growth in vitro by targeting the Wnt/β-catenin signaling pathway. J. Biol. Chem. 2014;289:35456-35467.
Not in our library10.1074/jbc.m114.621599
454.
Jaiswal AS, Marlow BP, Gupta N, Narayan S. Beta-catenin-mediated transactivation and cell-cell adhesion pathways are important in curcumin (diferuylmethane)-induced growth arrest and apoptosis in colon cancer cells. Oncogene. 2002;21:8414-8427.
Not in our library10.1038/sj.onc.1205947
455.
Prasad CP, Rath G, Mathur S, Bhatnagar D, Ralhan R. Potent growth suppressive activity of curcumin in human breast cancer cells: modulation of Wnt/beta-catenin signaling. Chem. Biol. Interact. 2009;181:263-271.
Not in our library10.1016/j.cbi.2009.06.012
456.
Leow P-C, Tian Q, Ong Z-Y, Yang Z, Ee P-LR. Antitumor activity of natural compounds, curcumin and PKF118-310, as Wnt/β-catenin antagonists against human osteosarcoma cells. Invest. N. Drugs. 2010;28:766-782.
Not in our library10.1007/s10637-009-9311-z
457.
Teiten M-H, et al. Anti-proliferative potential of curcumin in androgen-dependent prostate cancer cells occurs through modulation of the Wingless signaling pathway. Int. J. Oncol. 2011;38:603-611.
Not in our library10.3892/ijo.2011.905
458.
Hu P, et al. Both glypican-3/Wnt/β-catenin signaling pathway and autophagy contributed to the inhibitory effect of curcumin on hepatocellular carcinoma. Dig. Liver Dis. 2019;51:120-126.
Not in our library10.1016/j.dld.2018.06.012
459.
Kim HJ, Park SY, Park OJ, Kim Y-M. Curcumin suppresses migration and proliferation of Hep3B hepatocarcinoma cells through inhibition of the Wnt signaling pathway. Mol. Med. Rep. 2013;8:282-286.
Not in our library10.3892/mmr.2013.1497
460.
Wang J-Y, et al. Curcumin inhibits the growth via Wnt/β-catenin pathway in non-small-cell lung cancer cells. Eur. Rev. Med. Pharmacol. Sci. 2018;22:7492-7499.
Not in our library10.26355/eurrev_201811_16290
461.
Lu W, et al. Silibinin inhibits Wnt/β-catenin signaling by suppressing Wnt co-receptor LRP6 expression in human prostate and breast cancer cells. Cell. Signal. 2012;24:2291-2296.
Not in our library10.1016/j.cellsig.2012.07.009
462.
Silibinin Suppresses Growth of Human Colorectal Carcinoma SW480 Cells in Culture and Xenograft through Down-regulation of β-Catenin-Dependent Signaling · 2010
Not checked
463.
Zhang X, et al. Wnt blockers inhibit the proliferation of lung cancer stem cells. Drug Des. Devel. Ther. 2015;9:2399-2407.
Not in our library10.2147/dddt.s76602
464.
Zhu Y, et al. Rottlerin as a novel chemotherapy agent for adrenocortical carcinoma. Oncotarget. 2017;8:22825-22834.
Not in our library10.18632/oncotarget.15221
465.
Zhu J, et al. miR-19 targeting of GSK3β mediates sulforaphane suppression of lung cancer stem cells. J. Nutr. Biochem. 2017;44:80-91.
Not in our library10.1016/j.jnutbio.2017.02.020
466.
Du Y-Y, Liu X, Shan B-E. Periplocin extracted from cortex periplocae induces apoptosis of SW480 cells through inhibiting the Wnt/beta-catenin signaling pathway. Ai Zheng Aizheng Chin. J. Cancer. 2009;28:456-460.
Not in our library
467.
Li X, et al. Henryin, an ent-kaurane diterpenoid, inhibits Wnt signaling through interference with β-catenin/TCF4 interaction in colorectal cancer cells. PLoS ONE. 2013;8:e68525.
Not in our library10.1371/journal.pone.0068525
468.
Shrivastava, S. et al. Cardamonin, a chalcone, inhibits human triple negative breast cancer cell invasiveness by downregulation of Wnt/β-catenin signaling cascades and reversal of epithelial-mesenchymal transition. BioFactors43, 152–169 (2017).
Not in our library10.1002/biof.1315
469.
Williams SP, et al. Indirubins decrease glioma invasion by blocking migratory phenotypes in both the tumor and stromal endothelial cell compartments. Cancer Res. 2011;71:5374-5380.
Not in our library10.1158/0008-5472.can-10-3026
470.
Hui H, et al. Dihydroartemisinin suppresses growth of squamous cell carcinoma A431 cells by targeting the Wnt/β-catenin pathway. Anticancer. Drugs. 2016;27:99-105.
Not in our library10.1097/cad.0000000000000307
471.
Tang L, et al. Shizukaol D, a dimeric sesquiterpene isolated from Chloranthus serratus, represses the growth of human liver cancer cells by modulating Wnt signalling pathway. PLoS ONE. 2016;11:e0152012.
Not in our library10.1371/journal.pone.0152012
472.
Lee S-H, Richardson RL, Dashwood RH, Baek SJ. Capsaicin represses transcriptional activity of β-catenin in human colorectal cancer cells. J. Nutr. Biochem. 2012;23:646-655.
Not in our library10.1016/j.jnutbio.2011.03.009
473.
La de, R. M. et al. An intrinsically labile α-helix abutting the BCL9-binding site of β-catenin is required for its inhibition by carnosic acid. Nat. Commun. 3, 680 (2012).
Not in our library10.1038/ncomms1680
474.
Targeting GSK3 and Associated Signaling Pathways Involved in Cancer · 2020
No notice
475.
Osada T, et al. Antihelminth compound niclosamide downregulates Wnt signaling and elicits antitumor responses in tumors with activating APC mutations. Cancer Res. 2011;71:4172-4182.
Not in our library10.1158/0008-5472.can-10-3978
476.
Monin MB, et al. The anthelmintic niclosamide inhibits colorectal cancer cell lines via modulation of the canonical and noncanonical Wnt signaling pathway. J. Surg. Res. 2016;203:193-205.
Not in our library10.1016/j.jss.2016.03.051
477.
Arend RC, et al. Inhibition of Wnt/β-catenin pathway by niclosamide: a therapeutic target for ovarian cancer. Gynecol. Oncol. 2014;134:112-120.
Not in our library10.1016/j.ygyno.2014.04.005
478.
Niclosamide Suppresses Cancer Cell Growth By Inducing Wnt Co-Receptor LRP6 Degradation and Inhibiting the Wnt/β-Catenin Pathway · 2011
No notice
479.
Fako V, et al. Inhibition of wnt/β-catenin signaling in hepatocellular carcinoma by an antipsychotic drug pimozide. Int. J. Biol. Sci. 2016;12:768-775.
Not in our library10.7150/ijbs.14718
480.
Ren Y, Tao J, Jiang Z, Guo D, Tang J. Pimozide suppresses colorectal cancer via inhibition of Wnt/β-catenin signaling pathway. Life Sci. 2018;209:267-273.
Not in our library10.1016/j.lfs.2018.08.027
481.
Lu D, et al. Ethacrynic acid exhibits selective toxicity to chronic lymphocytic leukemia cells by inhibition of the Wnt/beta-catenin pathway. PLoS ONE. 2009;4:e8294.
Not in our library10.1371/journal.pone.0008294
482.
Wu W, et al. High LEF1 expression predicts adverse prognosis in chronic lymphocytic leukemia and may be targeted by ethacrynic acid. Oncotarget. 2016;7:21631-21643.
Not in our library10.18632/oncotarget.7795
483.
Al-Dali AM, Weiher H, Schmidt-Wolf IGH. Utilizing ethacrynic acid and ciclopirox olamine in liver cancer. Oncol. Lett. 2018;16:6854-6860.
Not in our library10.3892/ol.2018.9472
484.
Wu D, et al. Salinomycin inhibits proliferation and induces apoptosis of human nasopharyngeal carcinoma cell in vitro and suppresses tumor growth in vivo. Biochem. Biophys. Res. Commun. 2014;443:712-717.
Not in our library10.1016/j.bbrc.2013.12.032
485.
Wang F, et al. Salinomycin inhibits proliferation and induces apoptosis of human hepatocellular carcinoma cells in vitro and in vivo. PLoS ONE. 2012;7:e50638.
Not in our library10.1371/journal.pone.0050638
486.
Tai W-P, Hu P-J, Wu J, Lin X-C. The inhibition of Wnt/β-catenin signaling pathway in human colon cancer cells by sulindac. Tumori. 2014;100:97-101.
Not in our library10.1700/1430.15823
487.
Han A, et al. Sulindac suppresses beta-catenin expression in human cancer cells. Eur. J. Pharmacol. 2008;583:26-31.
Not in our library10.1016/j.ejphar.2007.12.034
488.
Huang C, et al. Celecoxib targets breast cancer stem cells by inhibiting the synthesis of prostaglandin E2 and down-regulating the Wnt pathway activity. Oncotarget. 2017;8:115254-115269.
Not in our library10.18632/oncotarget.23250
489.
Maier TJ, Janssen A, Schmidt R, Geisslinger G, Grösch S. Targeting the beta-catenin/APC pathway: a novel mechanism to explain the cyclooxygenase-2-independent anticarcinogenic effects of celecoxib in human colon carcinoma cells. FASEB. FASEB J. 2005;19:1353-1355.
Not in our library10.1096/fj.04-3274fje
490.
Deng Y, et al. Celecoxib downregulates CD133 expression through inhibition of the Wnt signaling pathway in colon cancer cells. Cancer Invest. 2013;31:97-102.
Not in our library10.3109/07357907.2012.754458
491.
Verkaar F, van der Doelen AA, Smits JFM, Blankesteijn WM, Zaman GJR. Inhibition of Wnt/β-catenin signaling by p38 MAP kinase inhibitors is explained by cross-reactivity with casein kinase Iδ/ɛ. Chem. Biol. 2011;18:485-494.
Not in our library10.1016/j.chembiol.2011.01.015
492.
Wang J-S, et al. Lithium inhibits proliferation of human esophageal cancer cell line Eca-109 by inducing a G2/M cell cycle arrest. World J. Gastroenterol. 2008;14:3982-3989.
Not in our library10.3748/wjg.14.3982
493.
Yeung J, et al. β-Catenin mediates the establishment and drug resistance of MLL leukemic stem cells. Cancer Cell. 2010;18:606-618.
Not in our library10.1016/j.ccr.2010.10.032
494.
Chon HJ, et al. Traf2- and Nck-interacting kinase (TNIK) is involved in the anti-cancer mechanism of dovitinib in human multiple myeloma IM-9 cells. Amino Acids. 2016;48:1591-1599.
Not in our library10.1007/s00726-016-2214-3
495.
Park S, Chun S. Streptonigrin inhibits β-catenin/Tcf signaling and shows cytotoxicity in β-catenin-activated cells. Biochim. Biophys. Acta. 2011;1810:1340-1345.
Not in our library10.1016/j.bbagen.2011.06.023

Cited by papers we hold 7

Wnt/β-catenin signaling pathway in carcinogenesis and cancer therapy · 2024
No notice
Role of the gut microbiota in anticancer therapy: from molecular mechanisms to clinical applications · 2023
No notice
Targeted therapy for head and neck cancer: signaling pathways and clinical studies · 2023
No notice
Intratumoral microbiota: roles in cancer initiation, development and therapeutic efficacy · 2023
No notice
Cellular mechanotransduction in health and diseases: from molecular mechanism to therapeutic targets · 2023
No notice
Integrin signaling in cancer: bidirectional mechanisms and therapeutic opportunities · 2023
No notice
Research progress of glutathione peroxidase family (GPX) in redoxidation · 2023
No notice

Reads

Read by people on this page

None yet.

Checked or read by AI through naulon

None yet.

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.

Are you an author?

Is this your paper?

Claim it to add your note and be paid when agents cite it. Free.