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Signaling Pathways in Cancer: Therapeutic Targets, Combinatorial Treatments, and New Developments

Hon Yan Kelvin Yip, Antonella Papa

Cells · 2021 · Review · CC BY

doi:10.3390/cells10030659

Abstract

Molecular alterations in cancer genes and associated signaling pathways are used to inform new treatments for precision medicine in cancer. Small molecule inhibitors and monoclonal antibodies directed at relevant cancer-related proteins have been instrumental in delivering successful treatments of some blood malignancies (e.g., imatinib with chronic myelogenous leukemia (CML)) and solid tumors (e.g., tamoxifen with ER positive breast cancer and trastuzumab for HER2-positive breast cancer). However, inherent limitations such as drug toxicity, as well as acquisition of de novo or acquired mechanisms of resistance, still cause treatment failure. Here we provide an up-to-date review of the successes and limitations of current targeted therapies for cancer treatment and highlight how recent technological advances have provided a new level of understanding of the molecular complexity underpinning resistance to cancer therapies. We also raise three basic questions concerning cancer drug discovery based on molecular markers and alterations of selected signaling pathways, and further discuss how combination therapies may become the preferable approach over monotherapy for cancer treatments. Finally, we consider novel therapeutic developments that may complement drug delivery and significantly improve clinical response and outcomes of cancer patients.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 20, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Introduction

Cancer is a disease characterized by the presence of cells undergoing continuous cell divisions in a rapid and uncontrolled manner. While in the early days surgery and chemotherapies were the only means available to treat tumors, the discovery of oncogenes and tumor suppressor genes has advanced the notion that single proteins can be targeted pharmacologically for cancer therapy. Recent advances in next-generation sequencing and multi-omics analyses have further revealed how signaling pathways are intimately intertwined to form complex circuitries within cells that, if fully mapped, can be exploited for more accurate targeted therapies.

In this review, we discuss some of the recent advances in cancer drug discovery and provide examples of signaling-based cancer therapies. We further discuss how synthetic lethality can be utilized to perturb “undruggable” targets, i.e., difficult to target proteins, and also to treat drug-resistant cancers. A large number of signaling nodes and molecular hubs have been implicated in the occurrence of cancer, and many of these, such as receptor tyrosine kinases (RTKs) and downstream signaling pathways, are current targets of drugs approved by multiple regulatory authorities (e.g., the U.S. Food and Drug Administration, FDA; European Medicines Agency, EMA).

2.1. Historical Perspective of Chemotherapy

Given the uncontrolled proliferative capacity distinctive of benign tumor and malignant cancer cells, local surgical resection and radiotherapy appeared to be a logical and effective way to treat tumors in the early days. However, tumors and cancers are more than just a mass of rapidly proliferating cells; they are indeed a highly complex disease that requires many elements to thrive, including a compromised microenvironment surrounding the primary tumor, as well as an adapted systemic response whereby a permissive immune system and microbiome allow the tumor to evolve. Additional factors such as intra-tumor heterogeneity and clonal evolution further challenge our appreciation of the complexity of tumor biology and dangerously undermine our ability to choose the most effective treatment at the point of care.

Modern chemotherapy began in the 1970s with the use of antimitotic drugs such as cyclophosphamide and chlorambucil, which were prescribed for the treatment of blood malignancies. Methotrexate, an anti-folate that inhibits dihydrofolate reductase and suppresses the synthesis of thymidine/purine, was prescribed to cancer patients in the 1980s. However, despite the initial positive response, patients became resistant to this antimitotic reagent and the disease inevitably relapsed. Since then, extensive drug-screening programs have been performed with the goal to identify new candidate targets for cancer treatment. Furthermore, because of the toxicity associated with the administration of poorly characterized drugs, it became clear that an understanding of the mechanisms through which anti-cancer drugs function is a key element in the pursuit of safe and effective cancer therapies.

2.2. Representative Signaling Pathways and Cancer

Since the early discovery of oncogenes (e.g., MYC, RAS, BRAF and KIT) and tumor suppressor genes (e.g., TP53, BRCA1 and PTEN), cancer-associated genetic lesions have been extensively documented. Nowadays, signaling pathways and molecular networks are recognized for their critical roles in executing and controlling important pro-survival and pro-growth cellular processes and are therefore chiefly implicated in the onset of cancer, and also in its potential treatment.

In this review, we will focus on a few signaling pathways and on selected types of cancer for which targeted therapies have significantly contributed to improve clinical outcomes. Two pathways in particular, the PI3K/AKT/mTOR signal transduction pathway and the Ras/MAPK pathway, are frequently activated or mutated in cancer. These cascades are highly interconnected in mediating upstream signals from receptor tyrosine kinases (RTKs) to intracellular effector proteins and cell cycle regulators. In addition to the linear signals propagated from the extracellular space into the cytoplasmic and nuclear compartments, the PI3K and MAPK pathways are strongly interconnected through a number of positive and negative feedback loops. As an example, targeted inhibition of mTORC1 through the administration of analogs of rapamycin, also known as rapalogs, can cause MAPK reactivation and can lead to resistance to single mTORC1 inhibition. Consequently, combinatorial targeting of mTOR plus MAPK has been shown to induce a better response to therapies.

Signaling pathways that regulate cell cycle progression (e.g., RTK-CDK4/6) and genomic stability (e.g., BRCA1, p53 and p21) are also frequently altered in cancer. Recent pan-cancer analyses have shown that chromosomal rearrangements, occurring as a result of genomic instability, are early events in various cancer types such as glioblastoma, melanoma, and breast adenocarcinoma. Consistently, CDK4/6 inhibitors and PARP inhibitors have been tested in a number of clinical trials for the treatment of cancer cells with compromised DNA repair, e.g., BRCA1/2 mutations. Furthermore, the growth of cancers expressing hormonal receptors, including breast, ovarian, and prostate cancers, has been shown to largely depend on the proliferative signal induced by their relative hormones, such as estrogen and androgen. The understanding of the mechanisms through which these nuclear hormones and their receptors function has led to the development of the diverse classes of inhibitors currently used as the standard of care for cancer treatment, as we detail below.

Notably, these selected examples do not include successes achieved through therapies directed at additional signaling pathways such as the apoptotic cascades. Moreover, emerging evidence suggests that the β-adrenergic receptor signaling, either at the level of the tumor macro-environment (e.g., adrenal medulla) or within the micro-environment (i.e., innervation by sympathetic nerve fibers within tumor tissues), can promote tumor progression and can be targeted by β-adrenergic antagonists and beta-blockers. Thus, these studies collectively show that after decades of intense genetic and biochemical studies, we have been able to identify a number of critical oncogenic alterations and exploit them for cancer treatment. This has tremendously improved our understanding of cancer biology and has also contributed to improving the overall survival rates of a number of cancer patients. Yet despite much progress, too often we find that even the most advanced targeted therapies still fail to effectively put cancer in remission.

3.1. Targeting Hormone Receptor Signaling through Endocrine Therapies

The first hormone therapy ever applied for cancer treatment was used in 1941 by Dr Charles Huggins, who administered estrogen and removed the testicles to lower the levels of testosterone in patients with prostate cancer. Ever since, endocrine therapies have been largely developed and used for the treatment and management of breast and prostate cancer.

Breast cancer (BC) is the second most common type of cancer affecting women worldwide. It is expected that almost 70% of newly diagnosed BC will depend on the pro-growth effect driven by the hormone estrogen and its receptor. The estrogen receptor (ER), which is a nuclear receptor able to transcribe pro-growth genes and to cross-talk with multiple receptor tyrosine kinases (RTK) and signaling pathways to sustain tumor cell growth. Given the high frequency of ER positive (ER+) BC, therapies suppressing the tumorigenic activity of this hormone are in continuous evolution. Several treatment approaches have been developed to inhibit estrogen action, and these include:aromatase inhibitors (e.g., letrozole, anastrozole, and exemestane), which inhibit estrogen production and levelsselective estrogen receptor modulators (SERMs) such as tamoxifen and toremifene, which bind to ER and form complexes with co-repressors instead of co-activators, thus halting the ER transcriptional programselective estrogen receptor degraders (SERDs) such as fulvestrant, which bind to ER, prevent its nuclear translocation, and lead to its subsequent degradation (Figure 1).

aromatase inhibitors (e.g., letrozole, anastrozole, and exemestane), which inhibit estrogen production and levels

selective estrogen receptor modulators (SERMs) such as tamoxifen and toremifene, which bind to ER and form complexes with co-repressors instead of co-activators, thus halting the ER transcriptional program

selective estrogen receptor degraders (SERDs) such as fulvestrant, which bind to ER, prevent its nuclear translocation, and lead to its subsequent degradation (Figure 1).

These therapies have dramatically improved outcomes and survival rates of breast cancer patients, and the five-year survival rate for ER+ breast cancer is now higher than 90%. However, despite the prolonged positive response to treatments, ER+ BC patients also develop resistance to hormone therapies over time, which can occur through multiple mechanisms. Loss of ER expression occurs in 10% of breast cancers, leading to a loss of treatment efficacy. Moreover, even when ER expression is still retained, molecular rewiring of the signaling pathways through the engagement of alternative RTKs such as EGFR, HER2, and FGFR can lead to the reactivation of ER-regulated transcription programs and tumor cell growth.

Multiple clinical trials are currently underway to identify combination therapies able to overcome resistance to ER targeted treatments. In an ongoing clinical trial (NCT01953926), the HER2 inhibitor neratinib, administered together with fulvestrant, increased progression-free survival compared to neratinib alone in ER+/HER2-mutant metastatic BC patients pre-treated with endocrine therapy. The FGFR inhibitors erdafitinib (NCT03238196) and TAS-120 (NCT04024436) have entered clinical trials in combination with fulvestrant to treat ER+ breast cancer with FGF amplification. The PI3K–AKT signaling pathway, which acts downstream of many RTKs, is frequently found constitutively active in BC, owing to mutations in PIK3CA and PTEN. Consistently, combinatorial use of fulvestrant with the PI3K p110α-specific inhibitor alpelisib has been approved for the treatment of ER+ metastatic breast cancer harboring PIK3CA mutations. Finally, a recent clinical trial testing the combinatorial effect of fulvestrant plus the AKT inhibitor capivasertib has also started..

Similar to breast cancer, prostate cancer (PCa) can also be driven by high levels of hormones such as androgens, whose synthesis is regulated by the hypothalamus–pituitary–testicular axis. PCa is one of the leading causes of death for men worldwide, and various therapeutic approaches have been developed to monitor and treat this slow-progressing tumor. After an initial active surveillance that can last several years, once the disease progresses from a low-risk and slow-growing tumor to a high-risk aggressive disease, prostatectomy and radiotherapy are generally proposed as the first line treatment. These initial treatments can be further followed up by androgen deprivation therapy (ADT) plus chemotherapy. If prostate cancer progresses to metastatic castration-resistant prostate cancer (mCRPC), this is then treated with antagonists of gonadotropin-releasing hormone and androgen receptor (AR), which, altogether, lower testosterone activities; abiraterone can be included in the treatment to further inhibit androgen synthesis.

Molecular profiling of PCa has identified three main mechanisms of resistance to ADT in CRPC. Hotspot point mutations in the ligand-binding domain of AR, such as the L702H, W742C, H875Y, and T878A mutations, are predominantly found in CRPC samples but not in primary PCa samples. Together with AR amplification, these missense mutations account for 60% of CRPC oncogenic mutations and function by rendering prostate cancer cells resistant to AR antagonists (e.g., hydroxyflutamide and enzalutamide) or by imposing agonist-bound structural conformations, which lead to the reactivation of AR signaling.

An additional mechanism of resistance to androgen deprivation is associated with residual levels of androgens produced by the activation of the de novo steroidogenesis pathway from cholesterol. Antiandrogen and steroidogenesis inhibitors such as enzalutamide and abiraterone are currently approved agents for CRPC treatment.

Finally, reports have shown that the activation of other steroid receptors can also contribute to treatment failure and PCa regrowth. The glucocorticoid receptor (GR)-regulated transcriptome highly overlaps with AR gene signatures, and compensatory activation of the GR signaling can lead to enzalutamide resistance in prostate cancer xenograft models. Furthermore, PIK3CA mutations and/or loss of PTEN, as well as Raf activation and DNA repair signaling pathways, have all been reported to contribute to the growth of metastatic CRPC through AR-independent mechanisms. Because of these events, a number of combinatorial treatments using ADT plus inhibitors directed at these signaling nodes are currently being tested in several clinical trials.

3.2. Targeting Receptor Tyrosine Kinases

Under physiologic conditions, RTKs can transduce growth-promoting signals to the cytoplasmic space. In cancer, RTKs can be found amplified, mutated, and constitutively active, thus causing growth signals to be continuously transduced even in the absence of upstream stimuli. To prevent this effect, monoclonal antibodies and targeted inhibitors have been developed.

Monoclonal antibodies (mAb) directed at the ecto-domains of RTKs act by binding and preventing RTKs interactions to their agonists. Cetuximab, a mAb binding EGFR, was the first FDA-approved monoclonal antibody used for the treatment of metastatic colorectal carcinoma. It functions by inducing receptor dimerization and internalization, thus reducing the overall EGFR protein levels on the plasma membrane. Given the frequency of EGFR activation in cancer, additional tyrosine kinase inhibitors, TKIs, directed at the cytoplasmic domain of EGFR have also been developed. To date, three generations of TKIs have been approved for use in clinics, including:first generation TKIs, gefitinib and erlotinib, which compete with ATP for the kinase domain of EGFR;second generation TKIs, e.g., afatinib and dacomitinib, with an improved affinity for the EGFR kinase domain; andthird generation TKIs, such as osimertinib, which covalently bind to cysteine residue on EGFR.

first generation TKIs, gefitinib and erlotinib, which compete with ATP for the kinase domain of EGFR;

second generation TKIs, e.g., afatinib and dacomitinib, with an improved affinity for the EGFR kinase domain; and

third generation TKIs, such as osimertinib, which covalently bind to cysteine residue on EGFR.

The second generation TKIs were shown to prolong the overall survival of patients with NSCLC treated with a first generation TKI, i.e., gefitinib plus chemotherapy. Unfortunately, acquisition of the EGFR T790M missense mutation, occurring in 50% of NSCLC, was found to cause structural changes in the EGFR binding pocket, thus rendering tumor cells resistant to the second generation of TKIs and requiring new treatments. The EGFR T790M-specific inhibitor osimertinib irreversibly binds to the C797 residue in the ATP-binding pocket of EGFR and has been found to improve progression-free survival (PFS) in patients with the acquired T790M mutation. Resistance to EGFR-targeted therapies, including osimertinib, can however still arise due to the activation of parallel RTKs such as HER2, MET, IGFR, FGFR, and PDGFR, or through the activation of downstream signaling pathways such as the PI3K–AKT and Ras–ERK pathways. Combinatorial targeting of EGFR and components of these signaling pathways may be a potential way of overcoming drug resistance to EGFR inhibition.

Human epidermal growth factor receptor 2 (HER2) is an EGFR family member frequently overexpressed in breast and gastric cancer. HER2 is an orphan receptor that does not have a direct ligand. When overexpressed, HER2 can form homodimers or heterodimers with other members of the EGFR family, and transduces the oncogenic signal to the PI3K–AKT and the Ras–ERK pathways. To target HER2 dimerization, and prevent its activation, mAbs such as trastuzumab and pertuzumab have been developed. HER2 can also be targeted with trastuzumab emtansine, which is a conjugate between trastuzumab and the cytotoxic reagent emtansine used to treat HER2+ breast and lung cancers. Bispecific antibodies such as ZW25, which binds to two HER2 epitopes (i.e., trastuzumab-binding domain and pertuzumab-binding domain), and MCLA-128, which targets HER2 and HER3, are now in clinical trials. These bispecific antibodies enhance HER2 internalization and better abrogate the HER2 oncogenic signal compared to trastuzumab. Finally, a more recent bispecific antibody, GBR1302, has been found to bind HER2 and CD3, and to direct cytotoxic T cells to HER2+ breast cancer cells.

In addition to mAbs, reversible TKIs, such as lapatinib, and the irreversible neratinib (pan-HER inhibitor) are also currently used in the clinic to halt signal transduction by blocking the phosphorylation of the HER2 kinase domain. However, due to the redundancy in signal transduction mediated by the many members of the HER family, incomplete inhibition of the signal can lead to resistance to targeted therapies. To overcome this, a combination of dual TKI lapatinib, or pan-TKI neratinib, plus mAbs has been shown to comprehensively block the known compensatory HER2 signaling network. Recently, tucatinib, a highly selective HER2 TKI, has been shown to inhibit HER2/HER3-mediated MAPK and PI3K/AKT signaling. It suppresses tumor growth and leads to tumor regression in HER2+ BT-474 breast xenograft models when used as monotherapy, or together with trastuzumab. Tucatinib has been recently approved by the FDA in combination with trastuzumab and capecitabine, an anti-metabolite, for the treatment of metastatic HER2+ breast cancer.

Activating HER2 point mutations (e.g., L755S, T862A, and T798M), and the truncated p95HER2 mutation, has been associated with resistance to HER2 therapies in breast cancer patients. Trastuzumab deruxtecan, an antibody-topoisomerase I inhibitor conjugate, effectively inhibits AKT phosphorylation, induces DNA damage, and suppresses the growth of HER2+ patient-derived xenografts (PDX) resistant to trastuzumab emtansine. Trastuzumab deruxtecan is now approved for the treatment of HER2+ breast cancer and gastric cancer patients.

Finally, alterations in PI3K and MAPK pathways have been shown to cause resistance to HER2-based therapies, and phase III clinical trials are now underway to treat advanced HER2+ breast cancer harboring PIK3CA mutations using the PI3K p110α-specific inhibitor alpelisib (NCT04208178).

3.3. Targeted Therapies Directed at the PI3K/AKT Signaling Pathway

The phosphoinositide 3-kinase (PI3K) signaling pathway plays an essential role in the regulation of cell proliferation, cell growth, and survival downstream of many RTKs (e.g., EGFR family; the insulin receptor, IR; and the insulin-like growth factor receptor, IGFR). RTKs can bind directly to PI3K or can signal through adaptor proteins such as the insulin receptor substrate 1 (IRS1). Multiple classes of PI3Ks exist but class IA PI3K is the most frequently mutated in cancer. Class IA PI3K (from now on just PI3K, unless specified) is a heterodimer consisting of a catalytic subunit, p110; and a regulatory subunit, p85. Upon binding to phospho-tyrosine residues on RTKs or IRS, p85 releases its inhibitory effect and activates p110, which in turn binds and phosphorylates the phosphatidylinositol-4,5-biphosphate (PtdIns-4,5-P2) to generate the second messenger phosphatidylinositol-3,4,5-triphosphate (PtdIns-3,4,5-P3 or PIP3). At the membrane, PIP3 recruits multiple downstream targets such as PDK1 and mTORC2, which catalyze AKT phosphorylation on Thr308 and Ser473, respectively. AKT is a central pro-survival signaling hub that regulates a plethora of downstream effector proteins including the mTORC1 complex, the FOXO family of transcription factors, and cyclin D1, and supports cell growth and proliferation. Multiple tumor suppressor proteins have been shown to limit PI3K pathway activation, such as the lipid and protein phosphatase PTEN, the promyelocytic leukemia protein PML, and the tuberous sclerosis complex TSC.

3.3.1. Targeting PI3K

Many members of the PI3K pathway are mutated in cancer, but PIK3CA and PTEN are the two critical players with the highest frequencies of alterations. PIK3CA, the gene encoding the p110α catalytic subunit of PI3K, is frequently mutated or amplified in endometrial, breast, ovarian, and colorectal cancer. Hotspot mutations in PIK3CA have been mapped to the exon 20, encoding the kinase domain (e.g., PIK3CA H1047R mutation) and the exon 9, encoding the helical domain (e.g., PIK3CA E542K, E545K mutations). These missense mutations render PI3K constitutively active and are frequently correlated with AKT activation.

Alterations in the tumor suppressor PTEN are found in somatic cancers such as breast, endometrial, prostate, and brain cancer, but they can also occur in the germline. where they cause various cancer-predisposition syndromes known as PTEN hamartoma tumor syndromes (PHTS). In addition to genomic loss or silencing, loss of PTEN function can frequently occur through acquisition of missense mutations. Importantly, through the generation of PTEN knock-in (KI) mouse models, our group and others have demonstrated that two frequent cancer-associated and loss-of-function PTEN mutations (i.e., PTEN G129E and C124S) can dimerize with wild-type PTEN and inhibit its function in a dominant negative manner. In vivo, these PTEN mutations cause more rapid tumor formation and progression than that observed in mice with PTEN heterozygous condition (PTEN+/− mice), suggesting that patients harboring these PTEN alterations may display heightened sensitivity to therapies directed at PI3K and/or AKT inhibition.

Early preclinical studies with the PI3K inhibitors Wortmannin and LY294002 suggested that the complete inhibition of all PI3K isoforms could provide a positive response to treatments in PIK3CA-mutant cancers. Over the years a number of pan-PI3K inhibitors such as buparlisib, pictilisib, pilaralisib, and copanlisib have been generated and also entered clinical trials. However, due to off-target toxicities, many of them have been discontinued, except for copanlisib, which has been approved by the FDA for the treatment of B-cell lymphomas with an altered PI3K pathway. Copanlisib is also in a phase II trial for the treatment of ER+/HER2- metastatic breast cancer patients (NCT03803761).

In order to reduce toxicity and increase treatment efficacy, isoform-selective PI3K inhibitors have been generated. The p110δ-specific inhibitor idelalisib, the first FDA-approved PI3K-isoform specific inhibitor, is nowadays used to treat chronic lymphocytic leukemia. More recently, the PI3Kα-specific inhibitor alpelisib has been approved for the treatment of ER+/HER2− PIK3CA-mutant and metastatic breast cancer in combination with fulvestrant. Taselisib is another PI3K inhibitor that equally inhibits p110α/γ/δ and has a 10-fold lower activity towards p110β. Preliminary results have suggested that taselisib suppresses the growth of PIK3CA-driven xenograft tumors and decreases both the activity and the levels of mutant p110α in vitro. Taselisib is now in a phase II clinical trial (NCT04439175) for both lymphomas and solid cancers with PIK3CA mutations.

The PI3K signaling pathway is frequently activated in solid tumors that have become insensitive to endocrine and RTK-targeted therapies. Because almost 40% of ER+ breast cancers harbor PIK3CA mutations, combination therapies using alpelisib or taselisib with endocrine therapies have been extensively tested in clinical trials. However, targeted PI3K inhibition has been shown to induce systemic metabolic adaptation, which impacts drug efficacy and limits tumor response to treatment. Because of this, PI3K-mutant specific inhibitors are now under development. GDC-0077, a PI3Kα inhibitor more selective towards mutant PI3K than wild-type PI3K, was found to induce proteasomal degradation of mutant PI3K, and caused tumor regression in PIK3CA-mutant breast cancer xenografts. This compound is now in clinical trial (NCT03006172) as a single agent, as well as in combination with other TKIs and endocrine therapy for the treatment of PIK3CA-mutant solid tumors.

Multiple mechanisms of resistance have been reported to cause treatment failure of PI3K inhibitors. For instance, the rewiring of the downstream signaling cascade can involve the reactivation of molecular targets such as mTOR, Pim1, PDK1/SGK1, or SGK3, all reported to support growth in an AKT-independent manner. Reactivation of additional p110 isoforms such as p110β has also been shown to sustain PIP3 accumulation and attenuate the growth inhibitory effect induced by p110α inhibition in PIK3CA-mutant and HER2-amplified breast cancer cells. Consistently, pre-clinical studies have shown that combined p110α and p110β inhibition can better suppress growth and induce tumor regression in PTEN-deficient breast and prostate cancer models than alpelisib alone.

PIK3CA mutations can co-occur with activating mutations in RTKs such as EGFR, KRAS, and ALK in lung adenocarcinomas, as well as with the loss of PTEN in endometrial and breast cancer. Juric et al. reported that PIK3CA-mutant breast cancer patients treated with alpelisib became refractory to treatment upon the acquired loss of PTEN. Treatments with the p110β inhibitor AZD6482 and alpelisib were shown to resensitize tumor cells and suppress the growth of PTEN-mutant PDX xenograft models. However, a recent clinical trial testing the efficacy of alpelisib with aromatase inhibitors (letrozole or exemestane) for PI3K-mutant ER+ metastatic breast cancer demonstrated that PTEN deletion, or loss-of-function PTEN mutations (e.g., PTEN A126S and PTEN R130 *) together with ESR1 activating mutations can still cooperate to cause treatment resistance.

Due to the high frequency of heterozygous deletion found in the PTEN genomic locus, reactivation of the remaining PTEN wild-type proteins has been considered an attractive approach for cancer therapy. The Pandolfi group has recently found that the ubiquitin E3 ligase 1 (WWP1) mediates PTEN poly-ubiquitination on lysine 27, which prevents PTEN dimerization, plasma membrane translocation, and activity toward PIP3. In turn, this abolishes PTEN tumor suppressive activity and favors cancer progression in a Myc-driven prostate cancer model. Authors further showed that indo-3-carbinol, a natural WWP1 inhibitor, can inhibit AKT activation and induces apoptosis in prostate organoids and tissues derived from Hi-Myc mutant mice, suggesting that WWP1 inhibition through the restoration of PTEN activity is synthetically lethal in Myc-driven tumors.

3.3.2. Targeting AKT

The proto-oncogene AKT, also known as protein kinase B, encompasses three isoforms (i.e., AKT1, AKT2 and AKT3), and promotes mTOR activation while suppressing p21/p27-mediated apoptosis. Constitutive activation of AKT, due to activating mutations in upstream RTKs, PI3K, and/or loss-of-function PTEN mutations, has been implicated in multiple cancers. Increased AKT activation has also been associated with resistance to chemotherapy and other TKIs, making AKT an attractive target for combination treatments. Ipatasertib (GDC-0068), an ATP-competitive pan-AKT inhibitor, synergizes with chemotherapeutic agents to inhibit growth and induce apoptosis in xenograft models of a spectrum of cancer cell lines, including breast, prostate, ovarian, and NSCLC cells. Moreover, PTEN deletion has been shown to sensitize MCF-10A breast cells and tumor xenografts to ipatasertib, suggesting that the loss of PTEN function can be a biomarker predicting the response to AKT inhibitors. Consistent with this, we have recently demonstrated that loss-of-function PTEN mutations (PTEN C124S/+ and PTEN G129E/+) coupled with oncogenic PI3K (PIK3CA H1047R) lead to AKT hyper-activation in a mouse model of breast cancer and that, although resistant to alpelisib, PTEN and PI3K mammary organoids are sensitive to the AKT inhibitor MK-2206.

Based on this large set of evidence, multiple clinical trials are now underway to evaluate the efficacy of combination therapies using AKT inhibitors with additional targeted therapies.

3.4. Targeted Therapies Directed at the Ras/MAPK Pathway

Activation of RTKs, such as the EGFR family, promotes activation of the guanosinetriphosphatase (GTPase) Ras proteins, which switch from their inactive Ras–GDP loaded state to the active Ras–GTP state. The Ras guanine nucleotide exchange factors (GEFs) catalyze the loading of GTP to RAS, whereas GTPase-activating proteins (GAPs) hydrolyze GTP–Ras to the GDP-bound inactive state. Ras activation recruits and activates downstream targets such as Raf, including A-Raf, B-Raf, and Raf-1, which are recruited to the plasma membrane through their Ras-binding domain (RBD) for dimerization and activation. Active Raf phosphorylates and activates MEK and ERK kinases, leading to ERK1/2 nuclear translocation and the promotion of transcriptional programs supporting cell growth, proliferation, or differentiation.

Multiple members of the MAPK pathway are mutated in cancer. KRAS is frequently mutated in solid tumors such as pancreatic ductal adenocarcinomas (82%), colorectal carcinomas (41%), and lung adenocarcinomas (32%). BRAF is mutated in 8% of human cancers, primarily melanoma, whereas MEK and ERK are rarely mutated. B-Raf/Raf-1 heterodimer is the predominant form of heterodimers transducing the Ras signal in cancer. The most prevalent activating mutation in BRAF occurs at the V600 position, which imposes an active conformation and can also transduce pro-growth signals as monomers in a Ras-independent manner.

The GTPase K-Ras oncoproteins have long been considered undruggable targets; however, recent developments have shown that new selective compounds can form covalent bonds with mutant KRASG12C, which accounts for 13% of all KRAS mutations, and inhibit KRAS activity. AMG510 and MRTX849 are two KRASG12C inhibitors currently being tested in clinical trials.

Three B-Raf inhibitors (i.e., dabrafenib, encorafenib, and vemurafenib) are available for the treatment of melanoma and NSCLC harboring the BRAFV600E/K mutations. B-Raf inhibitors specifically inhibit monomeric BRAFV600 mutant while their inhibitory potential towards dimeric Raf is reduced. Unexpectedly, B-Raf inhibitors have been reported to activate, instead of inhibit, the MAPK signaling in non-BRAFV600E tumor cells. It was found that by binding to B-Raf, these inhibitors increased the potential of wild-type Raf-1 to heterodimerize with B-Raf, thus sustaining high levels of pERK1/2 in a Ras-dependent manner.

In order to block the MAPK signaling in non-BRAFV600 tumor cells, type-II RAF inhibitors have been developed. Type-II RAF inhibitors can bind to B-Raf dimeric kinases and prevent Raf-1 transactivation, thus blocking downstream activation of MEK and ERK. Type-II Raf inhibitors such as PLX704 and PLX8394 are also called ‘paradox breaker’. They disrupt the formation of B-Raf homodimers/heterodimers and block the B-Raf-driven ERK signaling cascade in both BRAFV600 mutant and non-BRAFV600 mutant tumor cells.

Type-II Raf inhibitors can also overcome the ERK reactivation caused by vemurafenib treatments in vemurafenib-resistant melanoma cell lines. A pre-clinical study has shown that in combination with cetuximab, PLX8394 completely inhibited the growth of colorectal cancer PDXs with BRAF K601E and G466V mutants and resistant to vemurafenib.

Although the first generation of type-II RAF inhibitors (e.g., sorafenib and LY3009120) did not show significant activities in clinical trials, a new generation of pan-RAF inhibitors, e.g., AZ628, TAK632 and LXH254, have been developed and have been demonstrated to reduce phospho-MEK and phospho-ERK levels in the non-BRAFV600 mutant lung cancer H1666 cell line, in BRAF mutant human melanoma xenograft models, and human NSCLC xenograft models.

Resistance mechanisms to Raf inhibitors are usually due to genetic alterations within the MAPK pathway, such as KRAS/NRAS mutations, BRAFV600E/K amplification, and MEK1/2 amplification. Since Ras–GTPase activates both the MAPK and PI3K signaling pathways, activating mutations in the PI3K signaling pathways such as PTEN deletion and the constitutive activation of PI3K and AKT, it has been associated with resistance to Raf inhibition. Because RAS mutations can co-exist with mutations in members of the PI3K pathway, a simultaneous inhibition of both the MAPK and PI3K signaling pathways may overcome resistance to Raf inhibitors. Pre-clinical studies have shown that pan-PI3K inhibitors, AKT inhibitors, or mTOR inhibitors, in combination with MEK inhibitors, may deliver promising tumor suppressive effects in KRAS or BRAF-mutant tumors; however, the associated toxicity may still limit clinical benefits. An alternative approach to target both the PI3K/AKT and MAPK pathways is to combine the IGFR inhibitor, linsitinib, with the KRASG12C specific inhibitor, ARS-1620, and the mTOR inhibitor, everolimus. This three-drug combination was found to be better tolerated in clinical settings when each drug was administered at low dose.

Currently, there are three MEK1/2 inhibitors (binimetinib, trametinib, and cobimetinib) available for the treatment of melanoma and NSCLC harboring the BRAFV600E/K mutations. Next-generation MEK inhibitors are also available, such as RO5126766, which is defined as a dual Raf/MEK inhibitor that complexes with both proteins and inhibits phosphorylation of ERK in NRAS melanoma cells and in KRAS mutant xenograft models. This compound is currently under clinical trials to treat RAS mutant NSCLC (NCT03681483), and colorectal and ovarian cancer (NCT03875820). Since resistance to MEK inhibitions is usually due to reactivation of downstream ERK1/2, multiple ERK inhibitors such as ulixertinib (NCT04566393) and LY3214996 (NCT04391595) are also in clinical trials and may be considered as a valuable option to overcome resistance to FDA-approved MEK inhibitors.

3.5. Targeted Therapies Directed at Cyclin-Dependent Kinases

Cyclin-dependent kinases (CDKs) are kinases that complex with cyclins to initiate and regulate cell cycle progression. CDK activation is cell-cycle phase specific and is regulated by a few inhibitory proteins such as p16INK4A (CDKN2A), p15INK4B (CDKN2B), p18INK4C (CDKN2C), and p19INK4D (CDKN2D). Upon growth factor stimulation, the CDK4/6 complex binds to cyclin D1 and phosphorylates the retinoblastoma protein (RB), a master regulator of cell cycle entry and critical tumor suppressor (Figure 2). RB phosphorylation inhibits RB function and releases its inhibitory effect on the E2F transcription factor, thus promoting G1-S cell cycle transition. The CDK4/6 complex also activates FOXM1-mediated transcription, which plays an important role in the regulation of cell cycle progression and the suppression of cellular senescence.

Inhibitors targeting CDK4/6 activation (CDK4/6i) have made important progresses in breast cancer treatment. To date, there are three FDA-approved CDK4/6i in clinics: abemaciclib, ribociclib, and palbociclib. Except for abemaciclib, which can be used as monotherapy in refractory ER+/Her2- breast cancers, ribociclib and palbociclib are currently used in combination with aromatase inhibitors, or with fulvestrant for ER+ luminal breast cancers. Emerging evidence has shown that CDK4/6i can also regulate the host immune response and could therefore be used in combination with immune checkpoint inhibitors.

CDK4/6 inhibition effectively reverses drug resistance to endocrine therapies and RTK-based therapies. A screening of 47 breast cancer cell lines revealed that CDK4/6 inhibition suppresses the growth of ER+ luminal cancer and HER2+ cancer cell lines by inhibiting RB phosphorylation. More importantly, in combination with tamoxifen, palbociclib also resensitizes resistant MCF7 cells to tamoxifen. Miller and colleagues have shown that chronic deprivation of estrogen can lead to the hyper-activation of the PI3K/AKT signaling pathway and sustained CDK4-E2F activation, thus causing estrogen resistance in breast cancer cells. Consistently, a combinatorial drug screen of 42 compounds found that CDK4/6 inhibition exhibits the most significant synergism with PI3K inhibitors (BYL719 and GDC-0941) in a panel on PI3K-mutant breast cancer cell lines (T47D, MCF7, and MDA-MB-453) resistant to PI3K inhibition. Molecular studies found that high levels of pRB S780 may contribute to the resistance to PI3K inhibition in resistant cells in vitro, and in derived xenograft models. In agreement with this, combinatorial use of the CDK4/6 inhibitor LEE011 plus BYL719 or GDC-0941 caused tumor regression in breast cancer xenograft models.

Goel et al. have shown that CDK4/6 inhibition can also resensitize HER2-resistant breast cancer cells to trastuzumab, and that a combination of CDK4/6i abemaciclib with trastuzumab induces tumor regression in a HER2-driven breast cancer mouse model. Similarly, CDK4/6i can resensitize therapy-resistant tumors to EGFR inhibitors, MET/TRK inhibitors, and MEK inhibitors by suppressing the growth of tumor cells in multiple pre-clinical models, in vitro and in vivo.

Rewiring of cell-cycle regulators or activation of alternative pathways can however cause resistance to CDK4/6i. Although the status of RB can be used to predict sensitivity to CDK4/6i, genetic alterations in TP53, AKT1 and RAS, as well as overexpression of CDK4/6, CNNE1/2, and CDKN2A/2B, have been associated with CDK4/6i resistance. Amplifying or activating mutations in FGFR1/2 and ERBB2 have also been found to cause resistance to CDK4/6i. Genetic alterations in the Ras–ERK pathway and Hippo pathways may contribute to CDK4/6i resistance in prostate and breast cancer, respectively.

A recent study further revealed that loss of PTEN expression is a mechanism of adaptive resistance to CDK4/6i in breast cancer patients. Authors found that the PTEN knock-out (KO) in T47D cells caused resistance to ribociclib and palbociclib, but that administration of the AKT inhibitor MK-2206 resensitized PTEN-KO T47D cells to CDK4/6i, suggesting that AKT activation mediates the resistance to CDK4/6i in PTEN-deficient cells. Consistent with this, combinatorial treatment of ribociclib with MK-2206 induced tumor regression in PTEN-null T47D cells xenograft models.

3.6. Targeting Genomic Instability

DNA replication is a dynamic process under the active surveillance of cell cycle checkpoint inhibitors, which maintain the integrity of the genetic information during cell division. When DNA damage occurs in normal cells, multiple DNA damage response (DDR) pathways and mechanisms are induced. For instance, the base-excision repair (BER) and the nucleotide-excision repair machineries mediate single base-pair repair; homologous recombination (HR) and non-homologous end joining (NHEJ) can mediate repair on DNA double-strand breaks (DSB); and mitotic checkpoints ensure the correct centrosome localization and chromosomal segregation during cell division. Defects in these DNA repair mechanisms can lead to the induction of failsafe mechanisms, which act as additional checkpoints by inducing either a senescence response, or cell death.

However, upon the deletion of tumor suppressor genes or the activation of oncogenes, genomic instability can accumulate within cells and malignant transformation occurs. Mutations in DNA repair genes (e.g., BRCA1/2, PALB2, and RAD51C) and genome gatekeeper genes (e.g., TP53, ATM and CHEK2) are frequently found in cancer, and cancer cells with defective DDR or cell cycle checkpoints replicate damaged DNA to meet the uncontrolled proliferative drive induced by oncogenic signals.

Nevertheless, we have learnt how to exploit DNA damage accumulation by targeting DDR pathways and inducing mitotic catastrophe of cancer cells. Topoisomerase inhibitors (e.g., topotecan and etoposide) and DNA alkylating agents (e.g., cyclophosphamide and cisplatin) have long been used to induce cancer cell death, but targeted therapies directed at DDR pathways are still limited in use.

3.6.1. Targeting PARP to Exploit Defective HR Repair in Cancer

DNA double-strand breaks (DSB) can be repaired through either the error-free HR, or through the error-prone NHEJ repair mechanisms. In BRCA-expressing cells, HR is the predominant mode of DNA damage repair in the S/G2 phase. During DNA replication, DSBs are repaired by RAD51 recombinase, which uses the homologous sequence of the sister chromatid as template DNA. This process is facilitated by the BRCA1/BARD1 (BRCA1-associated RING domain protein 1) and BRCA2/PALB2 complexes. Unlike HR repair, the NHEJ machinery depends on the function of proteins such as Ku70/80 and the DNA-dependent protein kinase catalytic subunit (DNA-PKc) complex, which recruit ligases to repair DNA breaks. NHEJ is generally prone to introducing DNA deletions or insertions and is not used as the preferred pathway when a wild-type BRCA gene is expressed to ensure DNA integrity. However, when HR repair is not functional, such as upon BRCA loss, poly(adenosine diphosphate-ribose)ylation (PARylation) and NHEJ repair become the main DNA repair mechanisms. Defective HR repair is associated with germline mutations in BRCA1 and BRCA2, which frequently occur in hereditary breast and ovarian cancer. These mutations increase the lifetime risk of developing breast cancer from 12% to 46–87%, and ovarian cancer from 2% to 39–63%. BRCA2 pathogenic mutations are also associated with a 3.7-fold increase in the risk of developing prostate cancer.

PARylation is an early signal for sensing DNA damage. When cells undergo base-excision repair, the PAR polymerases, PARP1 and PARP2, are mobilized to DNA single-strand breaks where they synthesize branched PAR on acceptor proteins to stabilize the replication fork and facilitate the recruitment of DNA repair factors. PARP inhibitors (PARPi), now in multiple clinical trials, act by blocking PARP1 polymerase activity, which in turn traps and blocks the replisome from proceeding at the site of the DNA damage. This condition increases the load of the DNA damage in BRCA-mutated HR-deficient tumor cells, and leads to chromosomal abnormalities and mitotic catastrophe. PARPi such as olaparib, niraparib, talazoparib, and rucaparib have been approved for the treatment of HR-deficient breast and ovarian cancers, and since May 2020, they can also be used for the treatment of metastatic, castration-resistant prostate cancer.

However, a large fraction of human cancers are HR competent and are therefore unresponsive to PARP inhibition. To sensitize HR-proficient tumor cells to PARP inhibitors, a new combination treatment with the PI3K inhibitor has been tested. The pan-PI3K inhibitor BKM120 has been shown to induce the ETS-mediated downregulation of BRCA1/2, which depletes nucleotide triphosphate synthesis. Reduced nucleotides synthesis induces DNA damage and synergizes with PARP inhibitors in both HR-proficient and -deficient breast cancer mouse models. Based on pre-clinical results, a recent phase 1b trial has demonstrated synergism between olaparib and the PI3K p110α-specific inhibitor alpelisib in treating HR-proficient epithelial ovarian cancers. A recent study has also shown that simultaneous inhibition on PARP and EZH2, which mediates epigenetic silencing and suppresses NHEJ activity, can inhibit the growth of HR-proficient ovarian PDX models by inducing the NHEJ pathway and chromosomal abnormalities beyond repair, leading to apoptosis.

Resistance to PARPi is usually caused by the reactivation of the HR repair pathway. For example, restoration of BRCA1/BRCA2 activity due to reversion mutations, promoter demethylation, or the amplification of the mutant BRCA2 allele have all been associated with cancer resistance to PARPi. Additional proposed mechanisms of resistance to PARP inhibition in HR-deficient tumor cells have been recently reviewed.

In light of the resistance to PARP inhibitors, researchers have tried to combine PARPi with inhibitors that target the ATM (ataxia-telangiectasia mutated) and ATR (ATM- and Rad3-related) pathways, in order to block DDR pathways on multiple levels. Pre-clinical studies and clinical trials using replication/mitotic checkpoint inhibitors such as CHK1 inhibitors (UCN-01, LY2606368), ATR inhibitors (AZD6738), AURKA inhibitors (ENMD-2076), PLK inhibitors (Volasertib), and TTK inhibitors (BAY1161909) are currently being tested in combination with other inhibitors with the goal of causing replication stress and cell death of cancer cells.

Finally, PARylation turnover is a process regulated by poly(ADP-ribose) glycohydrolase (PARG), which degrades PAR chains to promote the firing of replication fork and cell cycle progression once DNA repair is complete. Inhibiting PARG would lead to the over-accumulation of PAR chains and eventually cause replication fork collapse and cell death. Pillay et al. demonstrated that the PARG inhibitor PDD00017273 showed synthetic lethality with the inhibition of a number of G2/M checkpoint proteins such as TIMELESS, HUS1 RFC2, ATR, WEE1, and CHK1. These combination treatments can cause replication catastrophe independent of BRCA1/2 status and therefore could be considered as an option to kill HR-proficient cells.

3.6.2. Targeting p53 and p21 to Induce Synthetic Lethality

TP53 is the most frequently mutated tumor suppressor gene in human malignancies, and because of its essential role in regulating genome stability it is also known as the guardian of the genome. Under physiologic conditions, p53 protein levels are restricted by the E3 ligase MDM2. However, upon cellular stress, the binding between MDM2 and p53 is disrupted, and p53 accumulation and activation occurs. The tumor suppressor p53 is a transcription factor that regulates the expression of critical genes such as CDKN1A, also known as p21, which induces cell cycle arrest and senescence, and BAX and PUMA, which promote apoptosis. Because of its central role in regulating cell cycle progression, forced p53 expression has long been considered a potential therapeutic approach for cancer treatment. Small molecule inhibitors such as nutlins and di-hydroisoquinolinones can disrupt the binding of MDM2 to p53, and their use has induced positive response in tumors retaining wild-type p53. Some of these compounds have entered clinical trials.

An alternative approach to exploiting p53 expression levels for cancer treatment is to identify contexts in which synthetic lethality can be achieved. For instance, ATR has been shown to maintain genomic stability by delaying cell cycle progression and preventing replication forks from collapsing. However, when ATR is inhibited, its downstream effector p53 becomes the predominant DDR mediator. Consistently, the ATR inhibitor AZD6738 was found to cause DNA damage followed by mitotic catastrophe in a p53- or ATM-defective context, as observed with chronic lymphocytic leukemia (CLL) cells. Moreover, p53 can promote 53BP1 (TP53-binding protein 1) recruitment to sites of DNA damage, thus excluding BRCA1 and inducing NHEJ. In p53-defective cells, reduced 53BP1 recruitment is accompanied by an increase of BRCA1 recruitment to sites of DNA damage, thus making HR the preferable mechanism of DNA repair. This suggests that p53-mutant cells may be sensitive to HR inhibition.

The CDK inhibitor p21WAF1/CIP1 is one of the p53-regulated genes mediating cell cycle arrest, apoptosis, and senescence in response to DNA damage. Histone deacetylase inhibitors can increase p21 expression and, when used in combination with cytotoxic agents, can induce cell death or cell cycle arrest in cancer cells such as hepatocellular carcinoma, ovarian cancer, and prostate cancer. Synthetic lethality has also been used to target p21. For example, p53-null colorectal cancer cells with low p21 expression are more sensitive to CHK1 inhibition.

However, new and conflicting data have shown that high p21 levels may also occur in cancer, which correlates with poor disease outcomes. A recent study has discovered a new population of Ki67+ dividing cells expressing high levels of p21 in head and neck squamous cell carcinomas, lung squamous cell carcinoma, and urothelial carcinomas. In addition, using the p53-null Saos-2 osteosarcoma cell line and p53-deficient Li–Fraumeni cell lines, Galanos et al. showed that high p21 levels influence the function of the CRL4–CDT2 ubiquitin ligase and increase levels of the licensing factors CDC6 and CDT1, which lead to defective origin licensing and replication stress, fueling genomic instability in cancer cells. It was found that cells with prolonged high p21 levels would eventually escape senescence and display aggressive phenotypes such as increased invasion and genotoxic drug tolerance. Mechanistically, high levels of p21 favored Rad52 recombinase-dependent break-induced replication (BIR) and single-strand annealing (SSA) as the main DNA repair mechanism over error-free synthesis-dependent strand annealing (SDSA). This suggests that targeting Rad52 may be synthetically lethal with high p21 levels in p53-null cancers. Additionally, clinically used treatments such as dexamethasone have also been found to induce p21 expression independent of p53, suggesting a detrimental use of this compound in patients with p53 deficiency. Indeed, both p53 mutations and high p21 levels have been demonstrated to exert oncogenic activities in cancer in a context dependent fashion.

3.7. Two Is Better Than One

Here we have summarized a number of known targeted therapies that affect the function of essential molecular hubs and are used to deliver better anti-cancer treatments. However, as we have detailed with various examples, signaling adaptation, acquired resistance, and novel defense mechanisms still allow cancer cells to survive and relapse. We propose that a better understanding of the “escape” mechanisms developing in cancer cells under treatment can provide new insights that can inform more effective combination therapies and will hopefully put cancer in a more stable remission.

4.1. Phosphoproteomics and Kinome Profiling

While genomic and transcriptomic sequencing projects have allowed the identification of genetic mutations and gene expression profiles associated with tumor initiation and progression, the molecular changes affecting the activation status of signaling pathways during cancer evolution still remain to be characterized. To identify pathological alterations of the signaling circuitries caused by reprogrammed signaling networks as a consequence of targeted therapies, proteomics and kinome profiling can provide alternative, though technically challenging, omics approaches.

Mass spectrometry-based phosphoproteomics is an unbiased approach to studying the phosphorylation events of proteins, and can provide detailed views of the activation status of various signaling nodes within cells. In contrast, kinome profiling uses multiple kinase inhibitors that, arranged in a top-down fashion inside a column, present varying specificities to protein substrates. Endogenous protein kinases that bind to these inhibitors are captured and analyzed by mass spectrometry to provide a global kinome representation. Phosphoproteomics-based methods have also been used to determine the activation states of kinases and to establish new kinase–phosphosite relationships. Comprehensive use of proteomics approaches for cancer therapeutics can be found in specialized reviews.

An understanding of how signaling networks adapt to perturbations induced by drug inhibitors, and how kinase–phosphosite relationships contribute to generate adapted signaling networks, can help design new combination therapies for cancer treatment.

Phosphoproteomics analyses have identified the CDK7/POLR2A axis as a new molecular node in patient-derived epithelial ovarian cancer (EOC), and it was shown that using the CDK7 inhibitor TZH1 suppressed the proliferation of EOC. Furthermore, Hijazi and colleagues used chemical phosphoproteomics to reveal that while PIK3CA wild-type cells seem to depend on MAPK pathway activation, PIK3CA mutant cells more predominantly rely on AKT and mTOR signaling outputs for survival. Moreover, phosphoproteomics analysis identified the protein kinase A (PKA)-regulated signaling network as pro-tumorigenic circuitry in G-protein α subunit (GNAS)-mutated small cell lung cancer cells. Through phosphoproteomics, we recently found that the loss of PTEN protein phosphatase activity leads to an enrichment of phospho-peptides regulated by the glucocorticoid receptor, GR, and confirmed that GR activation sensitizes mutant PTEN cells to death.

Kinome profiling can also be used to identify mechanisms associated with cancer drug resistance. Lee et al. showed that the phosphorylation of Y397 and Y576 on the focal adhesion kinase (FAK) is associated with resistance to docetaxel in a metastatic prostate cancer cell line, and that a combination therapy with FAK tyrosine kinase inhibitor can overcome the resistance. Moreover, it has been demonstrated that AURORA kinase A, AURKA, sustains mTOR phosphorylation levels in PIK3CA-mutated breast cancer cells treated with a pan-PI3K inhibitor or the AKT inhibitor MK-2206. AURKA inhibitors (e.g., MLN8237) were found to synergize with PI3K inhibitors to kill breast cancer cell lines in vitro and in xenograft models.

4.2. Functional Genomics for Cancer Therapy

Through functional genomics approaches, the cancer dependency map (DepMap) initiative (Broad Institute of MIT and Harvard) has used RNA interference (RNAi) and CRISPR/Cas9 loss-of-function gene-editing strategies to screen thousands of cancer cell lines and identify genes whose expression was found to be essential for cancer cell survival. By using genetic information (e.g., mutation, copy number variation, expression, and methylation profiles) from the cancer cell line encyclopedia (CCLE), scientists can now predict novel synthetic lethality and identify new molecular markers whose targeting can kill cancer cells harboring specific genetic mutations. As an example, inhibition of Egl nine homolog 1 (EGLN1) through the pan-EGLN1 inhibitor FG-4592 was found to selectively reduce the viability of HIF1A-high or ARID1A-mutant human ovarian cancer cell lines. Moreover, targeting of the Werner syndrome ATP-dependent helicase (WRN) was shown to effectively suppress the growth of microsatellite instable (MSI) colorectal and endometrial carcinoma cell lines.

The DepMap initiative also supports the repurposing of non-oncologic drugs by performing chemical perturbation viability screening. For instance, the alcohol dependence drug disulfiram was found to kill cancer cells with a reduced expression of metallothioneins. In a nutshell, this effort could save costs and time required for de novo drug developments.

4.3. Event-Driven Pharmacology: A Novel Approach to Inhibit Cancer-Associated Proteins

Occupancy-driven pharmacology is the mainstream drug discovery paradigm for cancer treatment. It relies on the use of small molecule inhibitors that occupy the functional-binding site of a protein and can disrupt protein interactions and their functions. Although small molecule inhibitors have been used in various cancer treatments, high doses of drug exposure are often required to maintain sufficient site occupancy in vivo. In turn, this can lead to off-target effects and unwanted toxicity. In contrast, event-driven pharmacology aims to target cancer-associated proteins, e.g., overexpressed or mutant proteins, and direct them to the ubiquitin–proteasome system (UPS) for elimination. Ubiquitination is a process by which misfolded or unfolded proteins are tagged with a chain of ubiquitin molecules to induce their degradation by the proteasome.

Proteolysis targeting chimeras (PROTACS) are bifunctional molecules containing a ligand-binding moiety linked to an E3 ligase-binding moiety. The ligand-binding moiety recognizes the protein of interest (POI) and brings it to the proximity of an E3 ligase to form a ternary complex. The ternary complex then allows for the ubiquitination and elimination of the POI while the PROTAC is recycled ready for the next round of action.

Recently, PROTACS have been shown to outperform occupancy-driven small molecule inhibitors for multiple reasons. First, PROTACS can recognize lysine residues on the surface of any protein, including commonly undruggable proteins such as transcription factors and scaffolding proteins, which would not be suitable targets for binding to small molecule inhibitors. Second, because PROTACS lead to the degradation of the POI, this process affects the catalytic activity as well as the potential scaffolding function of a protein. Moreover, after dissociating from the POI, PROTACS can cycle through multiple rounds of action and provide better pharmacokinetic profiles. There are around 600 different E3 ligases predicted in humans, which act in a tissue-specific and/or disease-specific manner and can therefore contribute to minimizing treatment-induced side effects while increasing the accuracy of targeted proteins. In fact, a recent proteomics study has shown that the VHL-based small molecule PROTAC can degrade ERRα and RIPK2 in tumor xenografts with nanomolar concentrations and showed limited off-target degradation effects.

Multiple cancer-related PROTACS have been developed so far, and these include PROTACS directed at EGFR, CDK4/6, ERK1/2, and PI3K. Notably, Hines and colleagues designed a phosphoPROTACS ErbB2PPPI3K directed at PI3K. The ErbB2PPPI3K consisted of a short stretch of ErbB3 intracellular domain bound to the SH2 domain of p85. Authors found that upon ErbB2/ErbB3 dimerization, the RTK phosphorylate ErbB2PPPI3K recruits PI3K for degradation and suppresses AKT activation in MCF7 breast cancer cells. It was found that INY-03-041 was able to inhibit PI3K/AKT signaling more effectively and potently than the PI3K inhibitor GDC-0068.

In addition, the E3 ligase cereblon (CRBN)-based PROTAC used palbociclib to selectively target CDK6 for degradation, suppressing both the kinase-dependent and independent activity of CDK6. Burslem et al. have also shown that lapatinib-coupled PROTAC can target HER2 for degradation, leading to more sustainable inhibition of HER3, AKT, and ERK1/2 phosphorylation compared to non-functional diastereomers (stereoisomer with different spatial arrangements), which were unable to degrade HER2. Similarly, c-Met-targeted PROTAC can inhibit downstream HGF signaling for longer times than its diastereomer. Interestingly, this PROTAC also induced the degradation of the exon 14 splice mutant of c-Met, which was shown to be resistant to endogenous proteasomal degradation. This important study suggests that PROTACS may be more efficient in inhibiting oncogenic signals than small molecule inhibitors because PROTACS can delay and reduce the kinome rewiring, thereby preventing the reactivation of compensatory oncogenic pathways.

Although most of the reported PROTACS have been directed at druggable targets, extending this approach to difficult-to-target proteins is an achievable goal that could induce potent degradation of oncogenic proteins even in conditions of low protein affinity.

5. Conclusions

After more than five decades of intense studies, cancer still remains an incurable disease for too many patients. Tremendous progresses have been made in the treatment of many types of cancer, and important goals have been reached that improved patients’ outcomes. Although resistance to therapies and disease recurrence remain main hurdles for cancer treatment and cure, successes in the treatment of some cancers, such as acute promyelocytic leukemia (APL), should inspire the next generation of scientists to persevere in their search for better combination treatments and improved outcomes. As we have briefly discussed, event-driven pharmacology and PROTACS are just one example of new possible approaches that have the potential to revolutionize the cancer drug-discovery field, which can further rely on combinations with immunotherapies. Technological developments can provide new tools that further expand our understanding of cancer and also its adaptation to current therapies. This knowledge, coupled with preventive cancer screening programs and better combination treatments, remain our best chance to treat cancer.

References 297

  1. 1.

    Waldman A.D., Fritz J.M., Lenardo M.J. A guide to cancer immunotherapy: From t cell basic science to clinical practice. Nat. Rev. Immunol. 2020;20:651-668.

    Not in our library10.1038/s41577-020-0306-5

  2. 2.

    Garner H., de Visser K.E. Immune crosstalk in cancer progression and metastatic spread: A complex conversation. Nat. Rev. Immunol. 2020;20:483-497.

    Not in our library10.1038/s41577-019-0271-z

  3. 3.

    Dai Z., Zhang J., Wu Q., Fang H., Shi C., Li Z., Lin C., Tang D., Wang D. Intestinal microbiota: A new force in cancer immunotherapy. Cell Commun. Signal. 2020;18:90.

    Not in our library10.1186/s12964-020-00599-6

  4. 4.

    Gilman A. The initial clinical trial of nitrogen mustard. Am. J. Surg. 1963;105:574-578.

    Not in our library10.1016/0002-9610(63)90232-0

  5. 5.

    Goodman L.S., Wintrobe M.M., Dameshek W. Nitrogen mustard therapy; use of methyl-bis (beta-chloroethyl) amine hydrochloride and tris (beta-chloroethyl) amine hydrochloride for hodgkin’s disease, lymphosarcoma, leukemia and certain allied and miscellaneous disorders. J. Am. Med. Assoc. 1946;132:126-132.

    Not in our library10.1001/jama.1946.02870380008004

  6. 6.

    Farber S., Diamond L.K. Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid. N. Engl. J. Med. 1948;238:787-793.

    Not in our library10.1056/nejm194806032382301

  7. 7.

    Bonadonna G., Brusamolino E., Valagussa P., Rossi A., Brugnatelli L., Brambilla C., De Lena M., Tancini G., Bajetta E., Musumeci R., et al. Combination chemotherapy as an adjuvant treatment in operable breast cancer. N. Engl. J. Med. 1976;294:405-410.

    Not in our library10.1056/nejm197602192940801

  8. 8.

    DeVita V.T., Chu E. A history of cancer chemotherapy. Cancer Res. 2008;68:8643-8653.

    Not in our library10.1158/0008-5472.can-07-6611

  9. 9.

    International Human Genome Sequencing Consortium. Finishing the euchromatic sequence of the human genome. Nature. 2004;431:931-945.

    Not in our library10.1038/nature03001

  10. 10.
    Pan-cancer analysis of whole genomes · 2020
    Corrected
  11. 11.

    Pons-Tostivint E., Thibault B., Guillermet-Guibert J. Targeting pi3k signaling in combination cancer therapy. Trends Cancer. 2017;3:454-469.

    Not in our library10.1016/j.trecan.2017.04.002

  12. 12.

    Janku F., Hong D.S., Fu S., Piha-Paul S.A., Naing A., Falchook G.S., Tsimberidou A.M., Stepanek V.M., Moulder S.L., Lee J.J., et al. Assessing pik3ca and pten in early-phase trials with pi3k/akt/mtor inhibitors. Cell Rep. 2014;6:377-387.

    Not in our library10.1016/j.celrep.2013.12.035

  13. 13.
    Androgen-targeted therapy in men with prostate cancer: evolving practice and future considerations · 2018
    No notice
  14. 14.

    Dutertre M., Smith C.L. Molecular mechanisms of selective estrogen receptor modulator (serm) action. J. Pharmacol. Exp. Ther. 2000;295:431-437.

    Not in our library

  15. 15.

    Carlson R.W. The history and mechanism of action of fulvestrant. Clin. Breast Cancer. 2005;6(Suppl. 1):S5-S8.

    Not in our library10.3816/cbc.2005.s.008

  16. 16.

    DiNardo C.D., Konopleva M.Y. A venetoclax bench-to-bedside story. Nat. Cancer. 2021;2:3-5.

    Not in our library10.1038/s43018-020-00165-6

  17. 17.

    Zahalka A.H., Frenette P.S. Nerves in cancer. Nat. Rev. Cancer. 2020;20:143-157.

    Not in our library10.1038/s41568-019-0237-2

  18. 18.

    Mravec B., Horvathova L., Hunakova L. Neurobiology of cancer: The role of beta-adrenergic receptor signaling in various tumor environments. Int. J. Mol. Sci. 2020;21:7958.

    Not in our library10.3390/ijms21217958

  19. 19.

    Huggins C., Hodges C.V. Studies on prostatic cancer. I. The effect of castration, of estrogen and androgen injection on serum phosphatases in metastatic carcinoma of the prostate. CA Cancer J. Clin. 1972;22:232-240.

    Not in our library10.3322/canjclin.22.4.232

  20. 20.

    Campbell R.A., Bhat-Nakshatri P., Patel N.M., Constantinidou D., Ali S., Nakshatri H. Phosphatidylinositol 3-kinase/akt-mediated activation of estrogen receptor alpha: A new model for anti-estrogen resistance. J. Biol. Chem. 2001;276:9817-9824.

    Not in our library10.1074/jbc.m010840200

  21. 21.

    DeSantis C.E., Ma J., Gaudet M.M., Newman L.A., Miller K.D., Goding Sauer A., Jemal A., Siegel R.L. Breast cancer statistics, 2019. CA Cancer J. Clin. 2019;69:438-451.

    Not in our library10.3322/caac.21583

  22. 22.

    Ma C.X., Reinert T., Chmielewska I., Ellis M.J. Mechanisms of aromatase inhibitor resistance. Nat. Rev. Cancer. 2015;15:261-275.

    Not in our library10.1038/nrc3920

  23. 23.

    Osborne C.K. Tamoxifen in the treatment of breast cancer. N. Engl. J. Med. 1998;339:1609-1618.

    Not in our library10.1056/nejm199811263392207

  24. 24.

    Wardell S.E., Marks J.R., McDonnell D.P. The turnover of estrogen receptor alpha by the selective estrogen receptor degrader (serd) fulvestrant is a saturable process that is not required for antagonist efficacy. Biochem. Pharmacol. 2011;82:122-130.

    Not in our library10.1016/j.bcp.2011.03.031

  25. 25.

    Hamilton E.P., Patel M.R., Armstrong A.C., Baird R.D., Jhaveri K., Hoch M., Klinowska T., Lindemann J.P.O., Morgan S.R., Schiavon G., et al. A first-in-human study of the new oral selective estrogen receptor degrader azd9496 for er(+)/her2(-) advanced breast cancer. Clin. Cancer Res. 2018;24:3510-3518.

    Not in our library10.1158/1078-0432.ccr-17-3102

  26. 26.

    Newby J.C., Johnston S.R., Smith I.E., Dowsett M. Expression of epidermal growth factor receptor and c-erbb2 during the development of tamoxifen resistance in human breast cancer. Clin. Cancer Res. 1997;3:1643-1651.

    Not in our library

  27. 27.

    Borg A., Baldetorp B., Ferno M., Killander D., Olsson H., Ryden S., Sigurdsson H. Erbb2 amplification is associated with tamoxifen resistance in steroid-receptor positive breast cancer. Cancer Lett. 1994;81:137-144.

    Not in our library10.1016/0304-3835(94)90194-5

  28. 28.

    Formisano L., Stauffer K.M., Young C.D., Bhola N.E., Guerrero-Zotano A.L., Jansen V.M., Estrada M.M., Hutchinson K.E., Giltnane J.M., Schwarz L.J., et al. Association of fgfr1 with eralpha maintains ligand-independent er transcription and mediates resistance to estrogen deprivation in er(+) breast cancer. Clin. Cancer Res. 2017;23:6138-6150.

    Not in our library10.1158/1078-0432.ccr-17-1232

  29. 29.

    Smyth L.M., Piha-Paul S.A., Won H.H., Schram A.M., Saura C., Loi S., Lu J., Shapiro G.I., Juric D., Mayer I.A., et al. Efficacy and determinants of response to her kinase inhibition in her2-mutant metastatic breast cancer. Cancer Discov. 2020;10:198-213.

    Not in our library10.1158/2159-8290.cd-19-0966

  30. 30.

    Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490:61-70.

    Not in our library10.1038/nature11412

  31. 31.

    Andre F., Ciruelos E., Rubovszky G., Campone M., Loibl S., Rugo H.S., Iwata H., Conte P., Mayer I.A., Kaufman B., et al. Alpelisib for pik3ca-mutated, hormone receptor-positive advanced breast cancer. N. Engl. J. Med. 2019;380:1929-1940.

    Not in our library10.1056/nejmoa1813904

  32. 32.

    Smyth L.M., Tamura K., Oliveira M., Ciruelos E.M., Mayer I.A., Sablin M.P., Biganzoli L., Ambrose H.J., Ashton J., Barnicle A., et al. Capivasertib, an akt kinase inhibitor, as monotherapy or in combination with fulvestrant in patients with akt1 (e17k)-mutant, er-positive metastatic breast cancer. Clin. Cancer Res. 2020;26:3947-3957.

    Not in our library10.1158/1078-0432.ccr-19-3953

  33. 33.

    Mottet N., Bellmunt J., Bolla M., Briers E., Cumberbatch M.G., De Santis M., Fossati N., Gross T., Henry A.M., Joniau S., et al. Eau-estro-siog guidelines on prostate cancer. Part 1: Screening, diagnosis, and local treatment with curative intent. Eur. Urol. 2017;71:618-629.

    Not in our library10.1016/j.eururo.2016.08.003

  34. 34.

    Van Poppel H., Nilsson S. Testosterone surge: Rationale for gonadotropin-releasing hormone blockers? Urology. 2008;71:1001-1006.

    Not in our library10.1016/j.urology.2007.12.070

  35. 35.

    Watson P.A., Arora V.K., Sawyers C.L. Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer. Nat. Rev. Cancer. 2015;15:701-711.

    Not in our library10.1038/nrc4016

  36. 36.

    Chen C.D., Welsbie D.S., Tran C., Baek S.H., Chen R., Vessella R., Rosenfeld M.G., Sawyers C.L. Molecular determinants of resistance to antiandrogen therapy. Nat. Med. 2004;10:33-39.

    Not in our library10.1038/nm972

  37. 37.

    Robinson D., Van Allen E.M., Wu Y.M., Schultz N., Lonigro R.J., Mosquera J.M., Montgomery B., Taplin M.E., Pritchard C.C., Attard G., et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161:1215-1228.

    Not in our library10.1016/j.cell.2015.05.001

  38. 38.
    Functional analysis of androgen receptor mutations that confer anti-androgen resistance identified in circulating cell-free DNA from prostate cancer patients · 2016
    No notice
  39. 39.

    Hara T., Miyazaki J., Araki H., Yamaoka M., Kanzaki N., Kusaka M., Miyamoto M. Novel mutations of androgen receptor: A possible mechanism of bicalutamide withdrawal syndrome. Cancer Res. 2003;63:149-153.

    Not in our library

  40. 40.

    Scher H.I., Fizazi K., Saad F., Taplin M.E., Sternberg C.N., Miller K., de Wit R., Mulders P., Chi K.N., Shore N.D., et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N. Engl. J. Med. 2012;367:1187-1197.

    Not in our library10.1056/nejmoa1207506

  41. 41.

    De Bono J.S., Logothetis C.J., Molina A., Fizazi K., North S., Chu L., Chi K.N., Jones R.J., Goodman O.B., Saad F., et al. Abiraterone and increased survival in metastatic prostate cancer. N. Engl. J. Med. 2011;364:1995-2005.

    Not in our library10.1056/nejmoa1014618

  42. 42.

    Arora V.K., Schenkein E., Murali R., Subudhi S.K., Wongvipat J., Balbas M.D., Shah N., Cai L., Efstathiou E., Logothetis C., et al. Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade. Cell. 2013;155:1309-1322.

    Not in our library10.1016/j.cell.2013.11.012

  43. 43.
    Recent Advances in Prostate Cancer Treatment and Drug Discovery · 2018
    No notice
  44. 44.

    Graham J., Muhsin M., Kirkpatrick P. Cetuximab. Nat. Rev. Drug Discov. 2004;3:549-550.

    Not in our library10.1038/nrd1445

  45. 45.

    Nguyen K.S., Kobayashi S., Costa D.B. Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancers dependent on the epidermal growth factor receptor pathway. Clin. Lung Cancer. 2009;10:281-289.

    Not in our library10.3816/clc.2009.n.039

  46. 46.

    Peters S., Zimmermann S., Adjei A.A. Oral epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of non-small cell lung cancer: Comparative pharmacokinetics and drug-drug interactions. Cancer Treat. Rev. 2014;40:917-926.

    Not in our library10.1016/j.ctrv.2014.06.010

  47. 47.

    Andrews Wright N.M., Goss G.D. Third-generation epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of non-small cell lung cancer. Transl. Lung Cancer Res. 2019;8:S247-S264.

    Not in our library10.21037/tlcr.2019.06.01

  48. 48.

    Wu Y.L., Zhou C., Hu C.P., Feng J., Lu S., Huang Y., Li W., Hou M., Shi J.H., Lee K.Y., et al. Afatinib versus cisplatin plus gemcitabine for first-line treatment of asian patients with advanced non-small-cell lung cancer harbouring egfr mutations (lux-lung 6): An open-label, randomised phase 3 trial. Lancet Oncol. 2014;15:213-222.

    Not in our library10.1016/s1470-2045(13)70604-1

  49. 49.

    Sequist L.V., Waltman B.A., Dias-Santagata D., Digumarthy S., Turke A.B., Fidias P., Bergethon K., Shaw A.T., Gettinger S., Cosper A.K., et al. Genotypic and histological evolution of lung cancers acquiring resistance to egfr inhibitors. Sci. Transl. Med. 2011;3:75ra26.

    Not in our library10.1126/scitranslmed.3002003

  50. 50.

    Janne P.A., Yang J.C., Kim D.W., Planchard D., Ohe Y., Ramalingam S.S., Ahn M.J., Kim S.W., Su W.C., Horn L., et al. Azd9291 in egfr inhibitor-resistant non-small-cell lung cancer. N. Engl. J. Med. 2015;372:1689-1699.

    Not in our library10.1056/nejmoa1411817

  51. 51.

    Soria J.C., Ohe Y., Vansteenkiste J., Reungwetwattana T., Chewaskulyong B., Lee K.H., Dechaphunkul A., Imamura F., Nogami N., Kurata T., et al. Osimertinib in untreated egfr-mutated advanced non-small-cell lung cancer. N. Engl. J. Med. 2018;378:113-125.

    Not in our library10.1056/nejmoa1713137

  52. 52.

    Planchard D., Loriot Y., Andre F., Gobert A., Auger N., Lacroix L., Soria J.C. Egfr-independent mechanisms of acquired resistance to azd9291 in egfr t790m-positive nsclc patients. Ann. Oncol. 2015;26:2073-2078.

    Not in our library10.1093/annonc/mdv319

  53. 53.

    Luo M., Fu L.W. Redundant kinase activation and resistance of egfr-tyrosine kinase inhibitors. Am. J. Cancer Res. 2014;4:608-628.

    Not in our library

  54. 54.

    Le X., Puri S., Negrao M.V., Nilsson M.B., Robichaux J., Boyle T., Hicks J.K., Lovinger K.L., Roarty E., Rinsurongkawong W., et al. Landscape of egfr-dependent and -independent resistance mechanisms to osimertinib and continuation therapy beyond progression in egfr-mutant nsclc. Clin. Cancer Res. 2018;24:6195-6203.

    Not in our library10.1158/1078-0432.ccr-18-1542

  55. 55.

    Ludovini V., Bianconi F., Pistola L., Chiari R., Minotti V., Colella R., Giuffrida D., Tofanetti F.R., Siggillino A., Flacco A., et al. Phosphoinositide-3-kinase catalytic alpha and kras mutations are important predictors of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in patients with advanced non-small cell lung cancer. J. Thorac. Oncol. 2011;6:707-715.

    Not in our library10.1097/jto.0b013e31820a3a6b

  56. 56.

    Douillard J.Y., Oliner K.S., Siena S., Tabernero J., Burkes R., Barugel M., Humblet Y., Bodoky G., Cunningham D., Jassem J., et al. Panitumumab-folfox4 treatment and ras mutations in colorectal cancer. N. Engl. J. Med. 2013;369:1023-1034.

    Not in our library10.1056/nejmoa1305275

  57. 57.

    Sanchez-Vega F., Mina M., Armenia J., Chatila W.K., Luna A., La K.C., Dimitriadoy S., Liu D.L., Kantheti H.S., Saghafinia S., et al. Oncogenic signaling pathways in the cancer genome atlas. Cell. 2018;173:321-337.e310.

    Not in our library10.1016/j.cell.2018.03.035

  58. 58.

    Rimawi M.F., Schiff R., Osborne C.K. Targeting her2 for the treatment of breast cancer. Annu. Rev. Med. 2015;66:111-128.

    Not in our library10.1146/annurev-med-042513-015127

  59. 59.

    Scheuer W., Friess T., Burtscher H., Bossenmaier B., Endl J., Hasmann M. Strongly enhanced antitumor activity of trastuzumab and pertuzumab combination treatment on her2-positive human xenograft tumor models. Cancer Res. 2009;69:9330-9336.

    Not in our library10.1158/0008-5472.can-08-4597

  60. 60.

    Amiri-Kordestani L., Blumenthal G.M., Xu Q.C., Zhang L., Tang S.W., Ha L., Weinberg W.C., Chi B., Candau-Chacon R., Hughes P., et al. Fda approval: Ado-trastuzumab emtansine for the treatment of patients with her2-positive metastatic breast cancer. Clin. Cancer Res. 2014;20:4436-4441.

    Not in our library10.1158/1078-0432.ccr-14-0012

  61. 61.

    Li B.T., Shen R., Buonocore D., Olah Z.T., Ni A., Ginsberg M.S., Ulaner G.A., Offin M., Feldman D., Hembrough T., et al. Ado-trastuzumab emtansine for patients with her2-mutant lung cancers: Results from a phase ii basket trial. J. Clin. Oncol. 2018;36:2532-2537.

    Not in our library10.1200/jco.2018.77.9777

  62. 62.

    Bartsch R., Bergen E. Asco 2018: Highlights in her2-positive metastatic breast cancer. Memo. 2018;11:280-283.

    Not in our library10.1007/s12254-018-0441-x

  63. 63.

    De Nardis C., Hendriks L.J.A., Poirier E., Arvinte T., Gros P., Bakker A.B.H., de Kruif J. A new approach for generating bispecific antibodies based on a common light chain format and the stable architecture of human immunoglobulin g1. J. Biol. Chem. 2017;292:14706-14717.

    Not in our library10.1074/jbc.m117.793497

  64. 64.

    De Vries Schultink A.H.M., Bol K., Doornbos R.P., Murat A., Wasserman E., Dorlo T.P.C., Schellens J.H.M., Beijnen J.H., Huitema A.D.R. Population pharmacokinetics of mcla-128, a her2/her3 bispecific monoclonal antibody, in patients with solid tumors. Clin. Pharm. 2020;59:875-884.

    Not in our library10.1007/s40262-020-00858-2

  65. 65.

    Geuijen C.A.W., De Nardis C., Maussang D., Rovers E., Gallenne T., Hendriks L.J.A., Visser T., Nijhuis R., Logtenberg T., de Kruif J., et al. Unbiased combinatorial screening identifies a bispecific igg1 that potently inhibits her3 signaling via her2-guided ligand blockade. Cancer Cell. 2018;33:922-936.e910.

    Not in our library10.1016/j.ccell.2018.04.003

  66. 66.

    Back J., Wermke M., Macoin J., Croset A., Kauh J.S., Reddy V. Gbr1302: Effect of cd3-her2, a bispecific t cell engager antibody, in trastuzumab-resistant cancers. J. Clin. Oncol. 2018;36:12053.

    Not in our library10.1200/jco.2018.36.15_suppl.12053

  67. 67.

    Chu I., Blackwell K., Chen S., Slingerland J. The dual erbb1/erbb2 inhibitor, lapatinib (gw572016), cooperates with tamoxifen to inhibit both cell proliferation- and estrogen-dependent gene expression in antiestrogen-resistant breast cancer. Cancer Res. 2005;65:18-25.

    Not in our library

  68. 68.

    Singh H., Walker A.J., Amiri-Kordestani L., Cheng J., Tang S., Balcazar P., Barnett-Ringgold K., Palmby T.R., Cao X., Zheng N., et al. U.S. Food and drug administration approval: Neratinib for the extended adjuvant treatment of early-stage her2-positive breast cancer. Clin. Cancer Res. 2018;24:3486-3491.

    Not in our library10.1158/1078-0432.ccr-17-3628

  69. 69.

    Martin M., Holmes F.A., Ejlertsen B., Delaloge S., Moy B., Iwata H., von Minckwitz G., Chia S.K.L., Mansi J., Barrios C.H., et al. Neratinib after trastuzumab-based adjuvant therapy in her2-positive breast cancer (extenet): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18:1688-1700.

    Not in our library10.1016/s1470-2045(17)30717-9

  70. 70.

    Yu L., Fu F., Li J., Huang M., Zeng B., Lin Y., Mei Q., Lv J., Wang C. Dual her2 blockade versus a single agent in trastuzumab-containing regimens for her2-positive early breast cancer: A systematic review and meta-analysis of randomized controlled trials. J. Oncol. 2020;2020:5169278.

    Not in our library10.1155/2020/5169278

  71. 71.

    Kulukian A., Lee P., Taylor J., Rosler R., de Vries P., Watson D., Forero-Torres A., Peterson S. Preclinical activity of her2-selective tyrosine kinase inhibitor tucatinib as a single agent or in combination with trastuzumab or docetaxel in solid tumor models. Mol. Cancer Ther. 2020;19:976-987.

    Not in our library10.1158/1535-7163.mct-19-0873

  72. 72.

    Murthy R.K., Loi S., Okines A., Paplomata E., Hamilton E., Hurvitz S.A., Lin N.U., Borges V., Abramson V., Anders C., et al. Tucatinib, trastuzumab, and capecitabine for her2-positive metastatic breast cancer. N. Engl. J. Med. 2020;382:597-609.

    Not in our library10.1056/nejmoa1914609

  73. 73.

    Christianson T.A., Doherty J.K., Lin Y.J., Ramsey E.E., Holmes R., Keenan E.J., Clinton G.M. Nh2-terminally truncated her-2/neu protein: Relationship with shedding of the extracellular domain and with prognostic factors in breast cancer. Cancer Res. 1998;58:5123-5129.

    Not in our library

  74. 74.

    Scaltriti M., Rojo F., Ocana A., Anido J., Guzman M., Cortes J., Di Cosimo S., Matias-Guiu X., Ramon y Cajal S., Arribas J., et al. Expression of p95her2, a truncated form of the her2 receptor, and response to anti-her2 therapies in breast cancer. J. Natl. Cancer Inst. 2007;99:628-638.

    Not in our library10.1093/jnci/djk134

  75. 75.

    Xu X., De Angelis C., Burke K.A., Nardone A., Hu H., Qin L., Veeraraghavan J., Sethunath V., Heiser L.M., Wang N., et al. Her2 reactivation through acquisition of the her2 l755s mutation as a mechanism of acquired resistance to her2-targeted therapy in her2(+) breast cancer. Clin. Cancer Res. 2017;23:5123-5134.

    Not in our library10.1158/1078-0432.ccr-16-2191

  76. 76.

    Modi S., Saura C., Yamashita T., Park Y.H., Kim S.B., Tamura K., Andre F., Iwata H., Ito Y., Tsurutani J., et al. Trastuzumab deruxtecan in previously treated her2-positive breast cancer. N. Engl. J. Med. 2020;382:610-621.

    Not in our library10.1056/nejmoa1914510

  77. 77.

    Keam S.J. Trastuzumab deruxtecan: First approval. Drugs. 2020;80:501-508.

    Not in our library10.1007/s40265-020-01281-4

  78. 78.

    Hyman D.M., Piha-Paul S.A., Won H., Rodon J., Saura C., Shapiro G.I., Juric D., Quinn D.I., Moreno V., Doger B., et al. Her kinase inhibition in patients with her2- and her3-mutant cancers. Nature. 2018;554:189-194.

    Not in our library10.1038/nature25475

  79. 79.

    Berns K., Horlings H.M., Hennessy B.T., Madiredjo M., Hijmans E.M., Beelen K., Linn S.C., Gonzalez-Angulo A.M., Stemke-Hale K., Hauptmann M., et al. A functional genetic approach identifies the pi3k pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell. 2007;12:395-402.

    Not in our library10.1016/j.ccr.2007.08.030

  80. 80.
    The PTEN–PI3K Axis in Cancer · 2019
    No notice
  81. 81.

    Hawkins P.T., Jackson T.R., Stephens L.R. Platelet-derived growth factor stimulates synthesis of ptdins(3,4,5)p3 by activating a ptdins(4,5)p2 3-oh kinase. Nature. 1992;358:157-159.

    Not in our library10.1038/358157a0

  82. 82.

    Stephens L.R., Hughes K.T., Irvine R.F. Pathway of phosphatidylinositol(3,4,5)-trisphosphate synthesis in activated neutrophils. Nature. 1991;351:33-39.

    Not in our library10.1038/351033a0

  83. 83.

    Alessi D.R., James S.R., Downes C.P., Holmes A.B., Gaffney P.R., Reese C.B., Cohen P. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase balpha. Curr. Biol. 1997;7:261-269.

    Not in our library10.1016/s0960-9822(06)00122-9

  84. 84.

    Whitman M., Downes C.P., Keeler M., Keller T., Cantley L. Type i phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositol-3-phosphate. Nature. 1988;332:644-646.

    Not in our library10.1038/332644a0

  85. 85.

    Sarbassov D.D., Guertin D.A., Ali S.M., Sabatini D.M. Phosphorylation and regulation of akt/pkb by the rictor-mtor complex. Science. 2005;307:1098-1101.

    Not in our library10.1126/science.1106148

  86. 86.

    Myers M.P., Pass I., Batty I.H., Van der Kaay J., Stolarov J.P., Hemmings B.A., Wigler M.H., Downes C.P., Tonks N.K. The lipid phosphatase activity of pten is critical for its tumor supressor function. Proc. Natl. Acad. Sci. USA. 1998;95:13513-13518.

    Not in our library10.1073/pnas.95.23.13513

  87. 87.

    Papa A., Cordon-Cardo C., Bernardi R., Pandolfi P.P. Compound in vivo inactivation of pml and p53 uncovers a functional interaction in angiosarcoma suppression. Genes Cancer. 2012;3:599-603.

    Not in our library10.1177/1947601912473604

  88. 88.

    Crino P.B., Nathanson K.L., Henske E.P. The tuberous sclerosis complex. N Engl. J. Med. 2006;355:1345-1356.

    Not in our library10.1056/nejmra055323

  89. 89.

    Thorpe L.M., Yuzugullu H., Zhao J.J. Pi3k in cancer: Divergent roles of isoforms, modes of activation and therapeutic targeting. Nat. Rev. Cancer. 2015;15:7-24.

    Not in our library10.1038/nrc3860

  90. 90.

    Zhang Y., Kwok-Shing Ng P., Kucherlapati M., Chen F., Liu Y., Tsang Y.H., de Velasco G., Jeong K.J., Akbani R., Hadjipanayis A., et al. A pan-cancer proteogenomic atlas of pi3k/akt/mtor pathway alterations. Cancer Cell. 2017;31:820-832.e823.

    Not in our library10.1016/j.ccell.2017.04.013

  91. 91.

    Kang S., Bader A.G., Vogt P.K. Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic. Proc. Natl. Acad. Sci. USA. 2005;102:802-807.

    Not in our library10.1073/pnas.0408864102

  92. 92.

    Isakoff S.J., Engelman J.A., Irie H.Y., Luo J., Brachmann S.M., Pearline R.V., Cantley L.C., Brugge J.S. Breast cancer-associated pik3ca mutations are oncogenic in mammary epithelial cells. Cancer Res. 2005;65:10992-11000.

    Not in our library10.1158/0008-5472.can-05-2612

  93. 93.

    Maehama T., Dixon J.E. The tumor suppressor, pten/mmac1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J. Biol. Chem. 1998;273:13375-13378.

    Not in our library10.1074/jbc.273.22.13375

  94. 94.

    Hobert J.A., Eng C. Pten hamartoma tumor syndrome: An overview. Genet. Med. 2009;11:687-694.

    Not in our library10.1097/gim.0b013e3181ac9aea

  95. 95.

    Ellison J., Driscoll D. Novel human pathological mutations. Gene symbol: Pten. Disease: Pten hamartoma tumour syndrome. Hum. Genet. 2010;127:124.

    Not in our library

  96. 96.

    Papa A., Wan L., Bonora M., Salmena L., Song M.S., Hobbs R.M., Lunardi A., Webster K., Ng C., Newton R.H., et al. Cancer-associated pten mutants act in a dominant-negative manner to suppress pten protein function. Cell. 2014;157:595-610.

    Not in our library10.1016/j.cell.2014.03.027

  97. 97.

    Heinrich F., Chakravarthy S., Nanda H., Papa A., Pandolfi P.P., Ross A.H., Harishchandra R.K., Gericke A., Losche M. The pten tumor suppressor forms homodimers in solution. Structure. 2015;23:1952-1957.

    Not in our library10.1016/j.str.2015.07.012

  98. 98.

    Wang H., Karikomi M., Naidu S., Rajmohan R., Caserta E., Chen H.Z., Rawahneh M., Moffitt J., Stephens J.A., Fernandez S.A., et al. Allele-specific tumor spectrum in pten knockin mice. Proc. Natl. Acad. Sci. USA. 2010;107:5142-5147.

    Not in our library10.1073/pnas.0912524107

  99. 99.
    Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems · 1999
    Not checked
  100. 100.

    Okada T., Sakuma L., Fukui Y., Hazeki O., Ui M. Blockage of chemotactic peptide-induced stimulation of neutrophils by wortmannin as a result of selective inhibition of phosphatidylinositol 3-kinase. J. Biol. Chem. 1994;269:3563-3567.

    Not in our library10.1016/s0021-9258(17)41900-4

  101. 101.

    Powis G., Bonjouklian R., Berggren M.M., Gallegos A., Abraham R., Ashendel C., Zalkow L., Matter W.F., Dodge J., Grindey G., et al. Wortmannin, a potent and selective inhibitor of phosphatidylinositol-3-kinase. Cancer Res. 1994;54:2419-2423.

    Not in our library

  102. 102.

    Vlahos C.J., Matter W.F., Hui K.Y., Brown R.F. A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4h-1-benzopyran-4-one (ly294002). J. Biol. Chem. 1994;269:5241-5248.

    Not in our library10.1016/s0021-9258(17)37680-9

  103. 103.

    Di Leo A., Johnston S., Lee K.S., Ciruelos E., Lonning P.E., Janni W., O’Regan R., Mouret-Reynier M.A., Kalev D., Egle D., et al. Buparlisib plus fulvestrant in postmenopausal women with hormone-receptor-positive, her2-negative, advanced breast cancer progressing on or after mtor inhibition (belle-3): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2018;19:87-100.

    Not in our library10.1016/s1470-2045(17)30688-5

  104. 104.

    Vuylsteke P., Huizing M., Petrakova K., Roylance R., Laing R., Chan S., Abell F., Gendreau S., Rooney I., Apt D., et al. Pictilisib pi3kinase inhibitor (a phosphatidylinositol 3-kinase [pi3k] inhibitor) plus paclitaxel for the treatment of hormone receptor-positive, her2-negative, locally recurrent, or metastatic breast cancer: Interim analysis of the multicentre, placebo-controlled, phase ii randomised peggy study. Ann. Oncol. 2016;27:2059-2066.

    Not in our library10.1093/annonc/mdw320

  105. 105.

    Abramson V.G., Supko J.G., Ballinger T., Cleary J.M., Hilton J.F., Tolaney S.M., Chau N.G., Cho D.C., Pearlberg J., Lager J., et al. Phase ib study of safety and pharmacokinetics of the pi3k inhibitor sar245408 with the her3-neutralizing human antibody sar256212 in patients with solid tumors. Clin. Cancer Res. 2017;23:3520-3528.

    Not in our library10.1158/1078-0432.ccr-16-1764

  106. 106.

    Patnaik A., Appleman L.J., Tolcher A.W., Papadopoulos K.P., Beeram M., Rasco D.W., Weiss G.J., Sachdev J.C., Chadha M., Fulk M., et al. First-in-human phase i study of copanlisib (bay 80-6946), an intravenous pan-class i phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors and non-hodgkin’s lymphomas. Ann. Oncol. 2016;27:1928-1940.

    Not in our library10.1093/annonc/mdw282

  107. 107.

    Sapon-Cousineau V., Sapon-Cousineau S., Assouline S. Pi3k inhibitors and their role as novel agents for targeted therapy in lymphoma. Curr. Treat. Options Oncol. 2020;21:51.

    Not in our library10.1007/s11864-020-00746-8

  108. 108.

    Miller B.W., Przepiorka D., de Claro R.A., Lee K., Nie L., Simpson N., Gudi R., Saber H., Shord S., Bullock J., et al. Fda approval: Idelalisib monotherapy for the treatment of patients with follicular lymphoma and small lymphocytic lymphoma. Clin. Cancer Res. 2015;21:1525-1529.

    Not in our library10.1158/1078-0432.ccr-14-2522

  109. 109.

    Juric D., Krop I., Ramanathan R.K., Wilson T.R., Ware J.A., Sanabria Bohorquez S.M., Savage H.M., Sampath D., Salphati L., Lin R.S., et al. Phase i dose-escalation study of taselisib, an oral pi3k inhibitor, in patients with advanced solid tumors. Cancer Discov. 2017;7:704-715.

    Not in our library10.1158/2159-8290.cd-16-1080

  110. 110.

    Song K.W., Edgar K.A., Kirkpatrick D.S., Phu L., Schmidt S., Nannini M., Hong R., Cheng E., Crocker L., Young A., et al. Abstract 146: The pi3k inhibitor, taselisib, has a unique mechanism of action that leads to enhanced potency in pik3ca mutant models. Cancer Res. 2017;77:146.

    Not in our library

  111. 111.

    Razavi P., Chang M.T., Xu G., Bandlamudi C., Ross D.S., Vasan N., Cai Y., Bielski C.M., Donoghue M.T.A., Jonsson P., et al. The genomic landscape of endocrine-resistant advanced breast cancers. Cancer Cell. 2018;34:427-438.e426.

    Not in our library10.1016/j.ccell.2018.08.008

  112. 112.

    Mayer I.A., Abramson V.G., Formisano L., Balko J.M., Estrada M.V., Sanders M.E., Juric D., Solit D., Berger M.F., Won H.H., et al. A phase ib study of alpelisib (byl719), a pi3kalpha-specific inhibitor, with letrozole in er+/her2- metastatic breast cancer. Clin. Cancer Res. 2017;23:26-34.

    Not in our library10.1158/1078-0432.ccr-16-0134

  113. 113.

    Mayer I.A., Prat A., Egle D., Blau S., Fidalgo J.A.P., Gnant M., Fasching P.A., Colleoni M., Wolff A.C., Winer E.P., et al. A phase ii randomized study of neoadjuvant letrozole plus alpelisib for hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer (neo-orb). Clin. Cancer Res. 2019;25:2975-2987.

    Not in our library10.1158/1078-0432.ccr-18-3160

  114. 114.

    Hopkins B.D., Pauli C., Du X., Wang D.G., Li X., Wu D., Amadiume S.C., Goncalves M.D., Hodakoski C., Lundquist M.R., et al. Suppression of insulin feedback enhances the efficacy of pi3k inhibitors. Nature. 2018;560:499-503.

    Not in our library10.1038/s41586-018-0343-4

  115. 115.

    Hong R., Edgar K., Song K., Steven S., Young A., Hamilton P., Arrazate A., De La Cruz C., Chan C., Pang J., et al. Abstract pd4-14: Gdc-0077 is a selective pi3kalpha inhibitor that demonstrates robust efficacy in pik3ca mutant breast cancer models as a single agent and in combination with standard of care therapies. Cancer Res. 2018;78.

    Not in our library10.1158/1538-7445.sabcs17-pd4-14

  116. 116.

    Edgar K., Hanan E., Staben S., Schmidt S., Hong R., Song K., Young A., Hamilton P., Arrazate A., Cruz C.d.l., et al. Abstract 156: Preclinical characterization of gdc-0077, a specific pi3k alpha inhibitor in early clinical development. Cancer Res. 2017;77:156.

    Not in our library

  117. 117.

    Juric D., Kalinsky K., Oliveira M., Cervantes A., Bedard P., Krop I., Hamilton E., Schmid P., Varga A., Turner N., et al. Abstract ot1-08-04: A first-in-human phase ia dose escalation study of gdc-0077, a p110a-selective and mutant-degrading pi3k inhibitor, in patients with pik3ca-mutant solid tumors. Cancer Res. 2020;80.

    Not in our library10.1158/1538-7445.sabcs19-ot1-08-04

  118. 118.

    Elkabets M., Vora S., Juric D., Morse N., Mino-Kenudson M., Muranen T., Tao J., Campos A.B., Rodon J., Ibrahim Y.H., et al. Mtorc1 inhibition is required for sensitivity to pi3k p110alpha inhibitors in pik3ca-mutant breast cancer. Sci. Transl. Med. 2013;5:196ra199.

    Not in our library10.1126/scitranslmed.3005747

  119. 119.

    Le X., Antony R., Razavi P., Treacy D.J., Luo F., Ghandi M., Castel P., Scaltriti M., Baselga J., Garraway L.A. Systematic functional characterization of resistance to pi3k inhibition in breast cancer. Cancer Discov. 2016;6:1134-1147.

    Not in our library10.1158/2159-8290.cd-16-0305

  120. 120.
    PDK1-SGK1 Signaling Sustains AKT-Independent mTORC1 Activation and Confers Resistance to PI3Kα Inhibition · 2016
    No notice
  121. 121.

    Gasser J.A., Inuzuka H., Lau A.W., Wei W., Beroukhim R., Toker A. Sgk3 mediates inpp4b-dependent pi3k signaling in breast cancer. Mol. Cell. 2014;56:595-607.

    Not in our library10.1016/j.molcel.2014.09.023

  122. 122.

    Vasudevan K.M., Barbie D.A., Davies M.A., Rabinovsky R., McNear C.J., Kim J.J., Hennessy B.T., Tseng H., Pochanard P., Kim S.Y., et al. Akt-independent signaling downstream of oncogenic pik3ca mutations in human cancer. Cancer Cell. 2009;16:21-32.

    Not in our library10.1016/j.ccr.2009.04.012

  123. 123.

    Costa C., Ebi H., Martini M., Beausoleil S.A., Faber A.C., Jakubik C.T., Huang A., Wang Y., Nishtala M., Hall B., et al. Measurement of pip3 levels reveals an unexpected role for p110beta in early adaptive responses to p110alpha-specific inhibitors in luminal breast cancer. Cancer Cell. 2015;27:97-108.

    Not in our library10.1016/j.ccell.2014.11.007

  124. 124.

    Hosford S.R., Dillon L.M., Bouley S.J., Rosati R., Yang W., Chen V.S., Demidenko E., Morra R.P., Miller T.W. Combined inhibition of both p110alpha and p110beta isoforms of phosphatidylinositol 3-kinase is required for sustained therapeutic effect in pten-deficient, er(+) breast cancer. Clin. Cancer Res. 2017;23:2795-2805.

    Not in our library10.1158/1078-0432.ccr-15-2764

  125. 125.

    Schwartz S., Wongvipat J., Trigwell C.B., Hancox U., Carver B.S., Rodrik-Outmezguine V., Will M., Yellen P., de Stanchina E., Baselga J., et al. Feedback suppression of pi3kalpha signaling in pten-mutated tumors is relieved by selective inhibition of pi3kbeta. Cancer Cell. 2015;27:109-122.

    Not in our library10.1016/j.ccell.2014.11.008

  126. 126.

    Chaft J.E., Arcila M.E., Paik P.K., Lau C., Riely G.J., Pietanza M.C., Zakowski M.F., Rusch V., Sima C.S., Ladanyi M., et al. Coexistence of pik3ca and other oncogene mutations in lung adenocarcinoma-rationale for comprehensive mutation profiling. Mol. Cancer Ther. 2012;11:485-491.

    Not in our library10.1158/1535-7163.mct-11-0692

  127. 127.

    Oda K., Okada J., Timmerman L., Rodriguez-Viciana P., Stokoe D., Shoji K., Taketani Y., Kuramoto H., Knight Z.A., Shokat K.M., et al. Pik3ca cooperates with other phosphatidylinositol 3’-kinase pathway mutations to effect oncogenic transformation. Cancer Res. 2008;68:8127-8136.

    Not in our library10.1158/0008-5472.can-08-0755

  128. 128.
    The somatic mutation profiles of 2,433 breast cancers refine their genomic and transcriptomic landscapes · 2016
    Corrected
  129. 129.

    Lazaridis G., Kotoula V., Vrettou E., Kostopoulos I., Manousou K., Papadopoulou K., Giannoulatou E., Bobos M., Sotiropoulou M., Pentheroudakis G., et al. Opposite prognostic impact of single pten-loss and pik3ca mutations in early high-risk breast cancer. Cancer Genom. Proteom. 2019;16:195-206.

    Not in our library10.21873/cgp.20125

  130. 130.

    Juric D., Castel P., Griffith M., Griffith O.L., Won H.H., Ellis H., Ebbesen S.H., Ainscough B.J., Ramu A., Iyer G., et al. Convergent loss of pten leads to clinical resistance to a pi(3)kalpha inhibitor. Nature. 2015;518:240-244.

    Not in our library10.1038/nature13948

  131. 131.

    Razavi P., Dickler M.N., Shah P.D., Toy W., Brown D.N., Won H.H., Li B.T., Shen R., Vasan N., Modi S., et al. Alterations in pten and esr1 promote clinical resistance to alpelisib plus aromatase inhibitors. Nat. Cancer. 2020;1:382-393.

    Not in our library10.1038/s43018-020-0047-1

  132. 132.

    Lee Y.R., Chen M., Lee J.D., Zhang J., Lin S.Y., Fu T.M., Chen H., Ishikawa T., Chiang S.Y., Katon J., et al. Reactivation of pten tumor suppressor for cancer treatment through inhibition of a myc-wwp1 inhibitory pathway. Science. 2019;364:eaau0159.

    Not in our library10.1126/science.aau0159

  133. 133.

    Abukhdeir A.M., Park B.H. P21 and p27: Roles in carcinogenesis and drug resistance. Expert Rev. Mol. Med. 2008;10:e19.

    Not in our library10.1017/s1462399408000744

  134. 134.
    Frequency and spectrum of PIK3CA somatic mutations in breast cancer · 2020
    No notice
  135. 135.

    Papa A., Pandolfi P.P. Modeling cancer-associated mutations of pten in mice. Methods Mol. Biol. 2016;1388:289-306.

    Not in our library10.1007/978-1-4939-3299-3_16

  136. 136.

    Liu L.Z., Zhou X.D., Qian G., Shi X., Fang J., Jiang B.H. Akt1 amplification regulates cisplatin resistance in human lung cancer cells through the mammalian target of rapamycin/p70s6k1 pathway. Cancer Res. 2007;67:6325-6332.

    Not in our library10.1158/0008-5472.can-06-4261

  137. 137.
    Convergent Akt activation drives acquired EGFR inhibitor resistance in lung cancer · 2017
    No notice
  138. 138.

    Lin J., Sampath D., Nannini M.A., Lee B.B., Degtyarev M., Oeh J., Savage H., Guan Z., Hong R., Kassees R., et al. Targeting activated akt with gdc-0068, a novel selective akt inhibitor that is efficacious in multiple tumor models. Clin. Cancer Res. 2013;19:1760-1772.

    Not in our library10.1158/1078-0432.ccr-12-3072

  139. 139.

    Yip H.Y.K., Chee A., Ang C.S., Shin S.Y., Ooms L.M., Mohammadi Z., Phillips W.A., Daly R.J., Cole T.J., Bronson R.T., et al. Control of glucocorticoid receptor levels by pten establishes a failsafe mechanism for tumor suppression. Mol. Cell. 2020;80:279-295.e278.

    Not in our library10.1016/j.molcel.2020.09.027

  140. 140.

    Kim S.B., Dent R., Im S.A., Espie M., Blau S., Tan A.R., Isakoff S.J., Oliveira M., Saura C., Wongchenko M.J., et al. Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (lotus): A multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2017;18:1360-1372.

    Not in our library10.1016/s1470-2045(17)30450-3

  141. 141.

    Oliveira M., Saura C., Nuciforo P., Calvo I., Andersen J., Passos-Coelho J.L., Gil Gil M., Bermejo B., Patt D.A., Ciruelos E., et al. Fairlane, a double-blind placebo-controlled randomized phase ii trial of neoadjuvant ipatasertib plus paclitaxel for early triple-negative breast cancer. Ann. Oncol. 2019;30:1289-1297.

    Not in our library10.1093/annonc/mdz177

  142. 142.

    Vetter I.R., Wittinghofer A. The guanine nucleotide-binding switch in three dimensions. Science. 2001;294:1299-1304.

    Not in our library10.1126/science.1062023

  143. 143.

    Mitin N., Rossman K.L., Der C.J. Signaling interplay in ras superfamily function. Curr. Biol. 2005;15:R563-R574.

    Not in our library10.1016/j.cub.2005.07.010

  144. 144.

    Malumbres M., Barbacid M. Ras oncogenes: The first 30 years. Nat. Rev. Cancer. 2003;3:459-465.

    Not in our library10.1038/nrc1097

  145. 145.

    Terrell E.M., Morrison D.K. Ras-mediated activation of the raf family kinases. Cold Spring Harb. Perspect Med. 2019;9:a033746.

    Not in our library10.1101/cshperspect.a033746

  146. 146.

    Desideri E., Cavallo A.L., Baccarini M. Alike but different: Raf paralogs and their signaling outputs. Cell. 2015;161:967-970.

    Not in our library10.1016/j.cell.2015.04.045

  147. 147.

    Moore A.R., Rosenberg S.C., McCormick F., Malek S. Ras-targeted therapies: Is the undruggable drugged? Nat. Rev. Drug Discov. 2020;19:533-552.

    Not in our library10.1038/s41573-020-0068-6

  148. 148.

    Weber C.K., Slupsky J.R., Kalmes H.A., Rapp U.R. Active ras induces heterodimerization of craf and braf. Cancer Res. 2001;61:3595-3598.

    Not in our library

  149. 149.

    Rushworth L.K., Hindley A.D., O’Neill E., Kolch W. Regulation and role of raf-1/b-raf heterodimerization. Mol. Cell Biol. 2006;26:2262-2272.

    Not in our library10.1128/mcb.26.6.2262-2272.2006

  150. 150.

    Canon J., Rex K., Saiki A.Y., Mohr C., Cooke K., Bagal D., Gaida K., Holt T., Knutson C.G., Koppada N., et al. The clinical kras(g12c) inhibitor amg 510 drives anti-tumour immunity. Nature. 2019;575:217-223.

    Not in our library10.1038/s41586-019-1694-1

  151. 151.

    Hallin J., Engstrom L.D., Hargis L., Calinisan A., Aranda R., Briere D.M., Sudhakar N., Bowcut V., Baer B.R., Ballard J.A., et al. The kras(g12c) inhibitor mrtx849 provides insight toward therapeutic susceptibility of kras-mutant cancers in mouse models and patients. Cancer Discov. 2020;10:54-71.

    Not in our library10.1158/2159-8290.cd-19-1167

  152. 152.

    Roskoski R. Properties of fda-approved small molecule protein kinase inhibitors: A 2020 update. Pharmacol. Res. 2020;152:104609.

    Not in our library10.1016/j.phrs.2019.104609

  153. 153.

    Hatzivassiliou G., Song K., Yen I., Brandhuber B.J., Anderson D.J., Alvarado R., Ludlam M.J., Stokoe D., Gloor S.L., Vigers G., et al. Raf inhibitors prime wild-type raf to activate the mapk pathway and enhance growth. Nature. 2010;464:431-435.

    Not in our library10.1038/nature08833

  154. 154.
    Kinase-Dead BRAF and Oncogenic RAS Cooperate to Drive Tumor Progression through CRAF · 2010
    No notice
  155. 155.

    Poulikakos P.I., Zhang C., Bollag G., Shokat K.M., Rosen N. Raf inhibitors transactivate raf dimers and erk signalling in cells with wild-type braf. Nature. 2010;464:427-430.

    Not in our library10.1038/nature08902

  156. 156.
    Targeting the Raf kinases in human cancer: the Raf dimer dilemma · 2017
    No notice
  157. 157.

    Karoulia Z., Wu Y., Ahmed T.A., Xin Q., Bollard J., Krepler C., Wu X., Zhang C., Bollag G., Herlyn M., et al. An integrated model of raf inhibitor action predicts inhibitor activity against oncogenic braf signaling. Cancer Cell. 2016;30:485-498.

    Not in our library10.1016/j.ccell.2016.06.024

  158. 158.

    Liu Y., Gray N.S. Rational design of inhibitors that bind to inactive kinase conformations. Nat. Chem. Biol. 2006;2:358-364.

    Not in our library10.1038/nchembio799

  159. 159.

    Zhang C., Spevak W., Zhang Y., Burton E.A., Ma Y., Habets G., Zhang J., Lin J., Ewing T., Matusow B., et al. Raf inhibitors that evade paradoxical mapk pathway activation. Nature. 2015;526:583-586.

    Not in our library10.1038/nature14982

  160. 160.

    Yao Z., Gao Y., Su W., Yaeger R., Tao J., Na N., Zhang Y., Zhang C., Rymar A., Tao A., et al. Raf inhibitor plx8394 selectively disrupts braf dimers and ras-independent braf-mutant-driven signaling. Nat. Med. 2019;25:284-291.

    Not in our library10.1038/s41591-018-0274-5

  161. 161.

    Noeparast A., Giron P., De Brakeleer S., Eggermont C., De Ridder U., Teugels E., De Greve J. Type ii raf inhibitor causes superior erk pathway suppression compared to type i raf inhibitor in cells expressing different braf mutant types recurrently found in lung cancer. Oncotarget. 2018;9:16110-16123.

    Not in our library10.18632/oncotarget.24576

  162. 162.

    Nakamura A., Arita T., Tsuchiya S., Donelan J., Chouitar J., Carideo E., Galvin K., Okaniwa M., Ishikawa T., Yoshida S. Antitumor activity of the selective pan-raf inhibitor tak-632 in braf inhibitor-resistant melanoma. Cancer Res. 2013;73:7043-7055.

    Not in our library10.1158/0008-5472.can-13-1825

  163. 163.

    Grasso M., Estrada M.A., Berrios K.N., Winkler J.D., Marmorstein R. N-(7-cyano-6-(4-fluoro-3-(2-(3-(trifluoromethyl)phenyl)acetamido)phenoxy)benzo[d] thiazol-2-yl)cyclopropanecarboxamide (tak632) promotes inhibition of braf through the induction of inhibited dimers. J. Med. Chem. 2018;61:5034-5046.

    Not in our library10.1021/acs.jmedchem.8b00499

  164. 164.

    Ramurthy S., Taft B.R., Aversa R.J., Barsanti P.A., Burger M.T., Lou Y., Nishiguchi G.A., Rico A., Setti L., Smith A., et al. Design and discovery of n-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluorom ethyl)isonicotinamide, a selective, efficacious, and well-tolerated raf inhibitor targeting ras mutant cancers: The path to the clinic. J. Med. Chem. 2020;63:2013-2027.

    Not in our library10.1021/acs.jmedchem.9b00161

  165. 165.

    Johnson D.B., Menzies A.M., Zimmer L., Eroglu Z., Ye F., Zhao S., Rizos H., Sucker A., Scolyer R.A., Gutzmer R., et al. Acquired braf inhibitor resistance: A multicenter meta-analysis of the spectrum and frequencies, clinical behaviour, and phenotypic associations of resistance mechanisms. Eur. J. Cancer. 2015;51:2792-2799.

    Not in our library10.1016/j.ejca.2015.08.022

  166. 166.

    Shi H., Moriceau G., Kong X., Lee M.K., Lee H., Koya R.C., Ng C., Chodon T., Scolyer R.A., Dahlman K.B., et al. Melanoma whole-exome sequencing identifies (v600e)b-raf amplification-mediated acquired b-raf inhibitor resistance. Nat. Commun. 2012;3:724.

    Not in our library10.1038/ncomms1727

  167. 167.

    Van Allen E.M., Wagle N., Sucker A., Treacy D.J., Johannessen C.M., Goetz E.M., Place C.S., Taylor-Weiner A., Whittaker S., Kryukov G.V., et al. The genetic landscape of clinical resistance to raf inhibition in metastatic melanoma. Cancer Discov. 2014;4:94-109.

    Not in our library10.1158/2159-8290.cd-13-0617

  168. 168.
    A Landscape of Pharmacogenomic Interactions in Cancer · 2016
    No notice
  169. 169.

    Shapiro G.I., LoRusso P., Kwak E., Pandya S., Rudin C.M., Kurkjian C., Cleary J.M., Pilat M.J., Jones S., de Crespigny A., et al. Phase ib study of the mek inhibitor cobimetinib (gdc-0973) in combination with the pi3k inhibitor pictilisib (gdc-0941) in patients with advanced solid tumors. Invest. New Drugs. 2020;38:419-432.

    Not in our library10.1007/s10637-019-00776-6

  170. 170.

    Bedard P.L., Tabernero J., Janku F., Wainberg Z.A., Paz-Ares L., Vansteenkiste J., Van Cutsem E., Perez-Garcia J., Stathis A., Britten C.D., et al. A phase ib dose-escalation study of the oral pan-pi3k inhibitor buparlisib (bkm120) in combination with the oral mek1/2 inhibitor trametinib (gsk1120212) in patients with selected advanced solid tumors. Clin. Cancer Res. 2015;21:730-738.

    Not in our library10.1158/1078-0432.ccr-14-1814

  171. 171.

    Tolcher A.W., Bendell J.C., Papadopoulos K.P., Burris H.A., Patnaik A., Jones S.F., Rasco D., Cox D.S., Durante M., Bellew K.M., et al. A phase ib trial of the oral mek inhibitor trametinib (gsk1120212) in combination with everolimus in patients with advanced solid tumors. Ann. Oncol. 2015;26:58-64.

    Not in our library10.1093/annonc/mdu482

  172. 172.

    Tolcher A.W., Patnaik A., Papadopoulos K.P., Rasco D.W., Becerra C.R., Allred A.J., Orford K., Aktan G., Ferron-Brady G., Ibrahim N., et al. Phase i study of the mek inhibitor trametinib in combination with the akt inhibitor afuresertib in patients with solid tumors and multiple myeloma. Cancer Chemother. Pharmacol. 2015;75:183-189.

    Not in our library10.1007/s00280-014-2615-5

  173. 173.

    Molina-Arcas M., Moore C., Rana S., van Maldegem F., Mugarza E., Romero-Clavijo P., Herbert E., Horswell S., Li L.S., Janes M.R., et al. Development of combination therapies to maximize the impact of kras-g12c inhibitors in lung cancer. Sci. Transl. Med. 2019;11:eaaw7999.

    Not in our library10.1126/scitranslmed.aaw7999

  174. 174.

    Ishii N., Harada N., Joseph E.W., Ohara K., Miura T., Sakamoto H., Matsuda Y., Tomii Y., Tachibana-Kondo Y., Iikura H., et al. Enhanced inhibition of erk signaling by a novel allosteric mek inhibitor, ch5126766, that suppresses feedback reactivation of raf activity. Cancer Res. 2013;73:4050-4060.

    Not in our library10.1158/0008-5472.can-12-3937

  175. 175.

    Wada M., Horinaka M., Yamazaki T., Katoh N., Sakai T. The dual raf/mek inhibitor ch5126766/ro5126766 may be a potential therapy for ras-mutated tumor cells. PLoS ONE. 2014;9:e113217.

    Not in our library10.1371/journal.pone.0113217

  176. 176.

    Trunzer K., Pavlick A.C., Schuchter L., Gonzalez R., McArthur G.A., Hutson T.E., Moschos S.J., Flaherty K.T., Kim K.B., Weber J.S., et al. Pharmacodynamic effects and mechanisms of resistance to vemurafenib in patients with metastatic melanoma. J. Clin. Oncol. 2013;31:1767-1774.

    Not in our library10.1200/jco.2012.44.7888

  177. 177.

    Roskoski R. Targeting erk1/2 protein-serine/threonine kinases in human cancers. Pharmacol Res. 2019;142:151-168.

    Not in our library10.1016/j.phrs.2019.01.039

  178. 178.

    Siebert R., Willers C.P., Opalka B. Role of the cyclin-dependent kinase 4 and 6 inhibitor gene family p15, p16, p18 and p19 in leukemia and lymphoma. Leuk. Lymphoma. 1996;23:505-520.

    Not in our library10.3109/10428199609054859

  179. 179.

    Malumbres M., Barbacid M. To cycle or not to cycle: A critical decision in cancer. Nat. Rev. Cancer. 2001;1:222-231.

    Not in our library10.1038/35106065

  180. 180.

    Sherr C.J. Mammalian g1 cyclins. Cell. 1993;73:1059-1065.

    Not in our library10.1016/0092-8674(93)90636-5

  181. 181.

    Anders L., Ke N., Hydbring P., Choi Y.J., Widlund H.R., Chick J.M., Zhai H., Vidal M., Gygi S.P., Braun P., et al. A systematic screen for cdk4/6 substrates links foxm1 phosphorylation to senescence suppression in cancer cells. Cancer Cell. 2011;20:620-634.

    Not in our library10.1016/j.ccr.2011.10.001

  182. 182.

    Hortobagyi G.N., Stemmer S.M., Burris H.A., Yap Y.S., Sonke G.S., Paluch-Shimon S., Campone M., Blackwell K.L., Andre F., Winer E.P., et al. Ribociclib as first-line therapy for hr-positive, advanced breast cancer. N. Engl. J. Med. 2016;375:1738-1748.

    Not in our library10.1056/nejmoa1609709

  183. 183.

    Rader J., Russell M.R., Hart L.S., Nakazawa M.S., Belcastro L.T., Martinez D., Li Y., Carpenter E.L., Attiyeh E.F., Diskin S.J., et al. Dual cdk4/cdk6 inhibition induces cell-cycle arrest and senescence in neuroblastoma. Clin. Cancer Res. 2013;19:6173-6182.

    Not in our library10.1158/1078-0432.ccr-13-1675

  184. 184.

    Tripathy D., Bardia A., Sellers W.R. Mechanism of action and clinical impact of ribociclib-response. Clin. Cancer Res. 2017;23:5658.

    Not in our library10.1158/1078-0432.ccr-17-1819

  185. 185.
    Efficacy and safety of palbociclib in combination with letrozole as first-line treatment of ER-positive, HER2-negative, advanced breast cancer: expanded analyses of subgroups from the randomized pivotal trial PALOMA-1/TRIO-18 · 2016
    No notice
  186. 186.

    Dickler M.N., Tolaney S.M., Rugo H.S., Cortes J., Dieras V., Patt D., Wildiers H., Hudis C.A., O’Shaughnessy J., Zamora E., et al. Monarch 1, a phase ii study of abemaciclib, a cdk4 and cdk6 inhibitor, as a single agent, in patients with refractory hr(+)/her2(-) metastatic breast cancer. Clin. Cancer Res. 2017;23:5218-5224.

    Not in our library10.1158/1078-0432.ccr-17-0754

  187. 187.
    Palbociclib plus letrozole as first-line therapy in estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer with extended follow-up · 2019
    No notice
  188. 188.

    Yu J., Yan J., Guo Q., Chi Z., Tang B., Zheng B., Yu J., Yin T., Cheng Z., Wu X., et al. Genetic aberrations in the cdk4 pathway are associated with innate resistance to pd-1 blockade in chinese patients with non-cutaneous melanoma. Clin. Cancer Res. 2019;25:6511-6523.

    Not in our library10.1158/1078-0432.ccr-19-0475

  189. 189.

    Goel S., DeCristo M.J., Watt A.C., BrinJones H., Sceneay J., Li B.B., Khan N., Ubellacker J.M., Xie S., Metzger-Filho O., et al. Cdk4/6 inhibition triggers anti-tumour immunity. Nature. 2017;548:471-475.

    Not in our library10.1038/nature23465

  190. 190.
    PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro · 2009
    No notice
  191. 191.

    Miller T.W., Balko J.M., Fox E.M., Ghazoui Z., Dunbier A., Anderson H., Dowsett M., Jiang A., Smith R.A., Maira S.M., et al. Eralpha-dependent e2f transcription can mediate resistance to estrogen deprivation in human breast cancer. Cancer Discov. 2011;1:338-351.

    Not in our library10.1158/2159-8290.cd-11-0101

  192. 192.

    Vora S.R., Juric D., Kim N., Mino-Kenudson M., Huynh T., Costa C., Lockerman E.L., Pollack S.F., Liu M., Li X., et al. Cdk 4/6 inhibitors sensitize pik3ca mutant breast cancer to pi3k inhibitors. Cancer Cell. 2014;26:136-149.

    Not in our library10.1016/j.ccr.2014.05.020

  193. 193.

    Goel S., Pernas S., Tan-Wasielewski Z., Barry W.T., Bardia A., Rees R., Andrews C., Tahara R.K., Trippa L., Mayer E.L., et al. Ribociclib plus trastuzumab in advanced her2-positive breast cancer: Results of a phase 1b/2 trial. Clin. Breast Cancer. 2019;19:399-404.

    Not in our library10.1016/j.clbc.2019.05.010

  194. 194.

    Zhou J., Wu Z., Wong G., Pectasides E., Nagaraja A., Stachler M., Zhang H., Chen T., Zhang H., Liu J.B., et al. Cdk4/6 or mapk blockade enhances efficacy of egfr inhibition in oesophageal squamous cell carcinoma. Nat. Commun. 2017;8:13897.

    Not in our library10.1038/ncomms13897

  195. 195.

    Foidart P., Yip C., Radermacher J., Blacher S., Lienard M., Montero-Ruiz L., Maquoi E., Montaudon E., Chateau-Joubert S., Collignon J., et al. Expression of mt4-mmp, egfr, and rb in triple-negative breast cancer strongly sensitizes tumors to erlotinib and palbociclib combination therapy. Clin. Cancer Res. 2019;25:1838-1850.

    Not in our library10.1158/1078-0432.ccr-18-1880

  196. 196.

    Olmez I., Zhang Y., Manigat L., Benamar M., Brenneman B., Nakano I., Godlewski J., Bronisz A., Lee J., Abbas T., et al. Combined c-met/trk inhibition overcomes resistance to cdk4/6 inhibitors in glioblastoma. Cancer Res. 2018;78:4360-4369.

    Not in our library10.1158/0008-5472.can-17-3124

  197. 197.
    Efficacy of the combination of MEK and CDK4/6 inhibitors in vitro and in vivo in KRAS mutant colorectal cancer models · 2016
    No notice
  198. 198.

    Pancholi S., Ribas R., Simigdala N., Schuster E., Nikitorowicz-Buniak J., Ressa A., Gao Q., Leal M.F., Bhamra A., Thornhill A., et al. Tumour kinome re-wiring governs resistance to palbociclib in oestrogen receptor positive breast cancers, highlighting new therapeutic modalities. Oncogene. 2020;39:4781-4797.

    Not in our library10.1038/s41388-020-1284-6

  199. 199.

    Li Z., Razavi P., Li Q., Toy W., Liu B., Ping C., Hsieh W., Sanchez-Vega F., Brown D.N., Da Cruz Paula A.F., et al. Loss of the fat1 tumor suppressor promotes resistance to cdk4/6 inhibitors via the hippo pathway. Cancer Cell. 2018;34:893-905.e898.

    Not in our library10.1016/j.ccell.2018.11.006

  200. 200.

    Wander S.A., Cohen O., Gong X., Johnson G.N., Buendia-Buendia J.E., Lloyd M.R., Kim D., Luo F., Mao P., Helvie K., et al. The genomic landscape of intrinsic and acquired resistance to cyclin-dependent kinase 4/6 inhibitors in patients with hormone receptor positive metastatic breast cancer. Cancer Discov. 2020;10:1174-1193.

    Not in our library10.1158/2159-8290.cd-19-1390

  201. 201.

    Finn R.S., Liu Y., Zhu Z., Martin M., Rugo H.S., Dieras V., Im S.A., Gelmon K.A., Harbeck N., Lu D.R., et al. Biomarker analyses of response to cyclin-dependent kinase 4/6 inhibition and endocrine therapy in women with treatment-naive metastatic breast cancer. Clin. Cancer Res. 2020;26:110-121.

    Not in our library10.1158/1078-0432.ccr-19-0751

  202. 202.

    Kettner N.M., Vijayaraghavan S., Durak M.G., Bui T., Kohansal M., Ha M.J., Liu B., Rao X., Wang J., Yi M., et al. Combined inhibition of stat3 and DNA repair in palbociclib-resistant er-positive breast cancer. Clin. Cancer Res. 2019;25:3996-4013.

    Not in our library10.1158/1078-0432.ccr-18-3274

  203. 203.

    Green J.L., Okerberg E.S., Sejd J., Palafox M., Monserrat L., Alemayehu S., Wu J., Sykes M., Aban A., Serra V., et al. Direct cdkn2 modulation of cdk4 alters target engagement of cdk4 inhibitor drugs. Mol. Cancer Ther. 2019;18:771-779.

    Not in our library10.1158/1535-7163.mct-18-0755

  204. 204.

    De Leeuw R., McNair C., Schiewer M.J., Neupane N.P., Brand L.J., Augello M.A., Li Z., Cheng L.C., Yoshida A., Courtney S.M., et al. Mapk reliance via acquired cdk4/6 inhibitor resistance in cancer. Clin. Cancer Res. 2018;24:4201-4214.

    Not in our library10.1158/1078-0432.ccr-18-0410

  205. 205.

    Costa C., Wang Y., Ly A., Hosono Y., Murchie E., Walmsley C.S., Huynh T., Healy C., Peterson R., Yanase S., et al. Pten loss mediates clinical cross-resistance to cdk4/6 and pi3kalpha inhibitors in breast cancer. Cancer Discov. 2020;10:72-85.

    Not in our library10.1158/2159-8290.cd-18-0830

  206. 206.

    Mani R.S., Chinnaiyan A.M. Triggers for genomic rearrangements: Insights into genomic, cellular and environmental influences. Nat. Rev. Genet. 2010;11:819-829.

    Not in our library10.1038/nrg2883

  207. 207.

    Crickard J.B., Moevus C.J., Kwon Y., Sung P., Greene E.C. Rad54 drives atp hydrolysis-dependent DNA sequence alignment during homologous recombination. Cell. 2020;181:1380-1394.e1318.

    Not in our library10.1016/j.cell.2020.04.056

  208. 208.

    Pace P., Mosedale G., Hodskinson M.R., Rosado I.V., Sivasubramaniam M., Patel K.J. Ku70 corrupts DNA repair in the absence of the fanconi anemia pathway. Science. 2010;329:219-223.

    Not in our library10.1126/science.1192277

  209. 209.

    Adamo A., Collis S.J., Adelman C.A., Silva N., Horejsi Z., Ward J.D., Martinez-Perez E., Boulton S.J., La Volpe A. Preventing nonhomologous end joining suppresses DNA repair defects of fanconi anemia. Mol. Cell. 2010;39:25-35.

    Not in our library10.1016/j.molcel.2010.06.026

  210. 210.

    Crasta K., Ganem N.J., Dagher R., Lantermann A.B., Ivanova E.V., Pan Y., Nezi L., Protopopov A., Chowdhury D., Pellman D. DNA breaks and chromosome pulverization from errors in mitosis. Nature. 2012;482:53-58.

    Not in our library10.1038/nature10802

  211. 211.

    Eischen C.M. Genome stability requires p53. Cold Spring Harb. Perspect Med. 2016;6:a026096.

    Not in our library10.1101/cshperspect.a026096

  212. 212.

    Lhota F., Zemankova P., Kleiblova P., Soukupova J., Vocka M., Stranecky V., Janatova M., Hartmannova H., Hodanova K., Kmoch S., et al. Hereditary truncating mutations of DNA repair and other genes in brca1/brca2/palb2-negatively tested breast cancer patients. Clin. Genet. 2016;90:324-333.

    Not in our library10.1111/cge.12748

  213. 213.

    Couch F.J., Hart S.N., Sharma P., Toland A.E., Wang X., Miron P., Olson J.E., Godwin A.K., Pankratz V.S., Olswold C., et al. Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. J. Clin. Oncol. 2015;33:304-311.

    Not in our library10.1200/jco.2014.57.1414

  214. 214.

    Chabner B.A., Roberts T.G. Timeline: Chemotherapy and the war on cancer. Nat. Rev. Cancer. 2005;5:65-72.

    Not in our library10.1038/nrc1529

  215. 215.

    Scully R., Chen J., Plug A., Xiao Y., Weaver D., Feunteun J., Ashley T., Livingston D.M. Association of brca1 with rad51 in mitotic and meiotic cells. Cell. 1997;88:265-275.

    Not in our library10.1016/s0092-8674(00)81847-4

  216. 216.

    Moynahan M.E., Chiu J.W., Koller B.H., Jasin M. Brca1 controls homology-directed DNA repair. Mol. Cell. 1999;4:511-518.

    Not in our library10.1016/s1097-2765(00)80202-6

  217. 217.

    Blackford A.N., Jackson S.P. Atm, atr, and DNA-pk: The trinity at the heart of the DNA damage response. Mol. Cell. 2017;66:801-817.

    Not in our library10.1016/j.molcel.2017.05.015

  218. 218.

    Zhao W., Steinfeld J.B., Liang F., Chen X., Maranon D.G., Jian Ma C., Kwon Y., Rao T., Wang W., Sheng C., et al. Brca1-bard1 promotes rad51-mediated homologous DNA pairing. Nature. 2017;550:360-365.

    Not in our library10.1038/nature24060

  219. 219.

    Chapman J.R., Sossick A.J., Boulton S.J., Jackson S.P. Brca1-associated exclusion of 53bp1 from DNA damage sites underlies temporal control of DNA repair. J. Cell Sci. 2012;125:3529-3534.

    Not in our library10.1242/jcs.105353

  220. 220.

    Patel A.G., Sarkaria J.N., Kaufmann S.H. Nonhomologous end joining drives poly(adp-ribose) polymerase (parp) inhibitor lethality in homologous recombination-deficient cells. Proc. Natl. Acad. Sci. USA. 2011;108:3406-3411.

    Not in our library10.1073/pnas.1013715108

  221. 221.

    Petrucelli N., Daly M.B., Pal T., Adam M.P., Ardinger H.H., Pagon R.A., Wallace S.E., Bean L.J.H., Stephens K., Amemiya A. Brca1- and brca2-associated hereditary breast and ovarian cancer. Genereviews((r)). 1993.

    Not in our library

  222. 222.

    Gibson B.A., Kraus W.L. Identification of protein substrates of specific parp enzymes using analog-sensitive parp mutants and a “clickable” nad(+) analog. Methods Mol. Biol. 2017;1608:111-135.

    Not in our library10.1007/978-1-4939-6993-7_9

  223. 223.

    Ray Chaudhuri A., Nussenzweig A. The multifaceted roles of parp1 in DNA repair and chromatin remodelling. Nat. Rev. Mol. Cell Biol. 2017;18:610-621.

    Not in our library10.1038/nrm.2017.53

  224. 224.

    Murai J., Huang S.Y., Das B.B., Renaud A., Zhang Y., Doroshow J.H., Ji J., Takeda S., Pommier Y. Trapping of parp1 and parp2 by clinical parp inhibitors. Cancer Res. 2012;72:5588-5599.

    Not in our library10.1158/0008-5472.can-12-2753

  225. 225.

    Lord C.J., Ashworth A. Parp inhibitors: Synthetic lethality in the clinic. Science. 2017;355:1152-1158.

    Not in our library10.1126/science.aam7344

  226. 226.

    De Bono J., Kang J., Hussain M. Olaparib for metastatic castration-resistant prostate cancer. Reply. N. Engl. J. Med. 2020;383:891.

    Not in our library10.1056/nejmc2023199

  227. 227.

    Juvekar A., Burga L.N., Hu H., Lunsford E.P., Ibrahim Y.H., Balmana J., Rajendran A., Papa A., Spencer K., Lyssiotis C.A., et al. Combining a pi3k inhibitor with a parp inhibitor provides an effective therapy for brca1-related breast cancer. Cancer Discov. 2012;2:1048-1063.

    Not in our library10.1158/2159-8290.cd-11-0336

  228. 228.

    Ibrahim Y.H., Garcia-Garcia C., Serra V., He L., Torres-Lockhart K., Prat A., Anton P., Cozar P., Guzman M., Grueso J., et al. Pi3k inhibition impairs brca1/2 expression and sensitizes brca-proficient triple-negative breast cancer to parp inhibition. Cancer Discov. 2012;2:1036-1047.

    Not in our library10.1158/2159-8290.cd-11-0348

  229. 229.

    Konstantinopoulos P.A., Barry W.T., Birrer M., Westin S.N., Cadoo K.A., Shapiro G.I., Mayer E.L., O’Cearbhaill R.E., Coleman R.L., Kochupurakkal B., et al. Olaparib and alpha-specific pi3k inhibitor alpelisib for patients with epithelial ovarian cancer: A dose-escalation and dose-expansion phase 1b trial. Lancet Oncol. 2019;20:570-580.

    Not in our library10.1016/s1470-2045(18)30905-7

  230. 230.

    Karakashev S., Fukumoto T., Zhao B., Lin J., Wu S., Fatkhutdinov N., Park P.H., Semenova G., Jean S., Cadungog M.G., et al. Ezh2 inhibition sensitizes carm1-high, homologous recombination proficient ovarian cancers to parp inhibition. Cancer Cell. 2020;37:157-167.e156.

    Not in our library10.1016/j.ccell.2019.12.015

  231. 231.

    Gornstein E.L., Sandefur S., Chung J.H., Gay L.M., Holmes O., Erlich R.L., Soman S., Martin L.K., Rose A.V., Stephens P.J., et al. Brca2 reversion mutation associated with acquired resistance to olaparib in estrogen receptor-positive breast cancer detected by genomic profiling of tissue and liquid biopsy. Clin. Breast Cancer. 2018;18:184-188.

    Not in our library10.1016/j.clbc.2017.12.010

  232. 232.

    Lheureux S., Bruce J.P., Burnier J.V., Karakasis K., Shaw P.A., Clarke B.A., Yang S.Y., Quevedo R., Li T., Dowar M., et al. Somatic brca1/2 recovery as a resistance mechanism after exceptional response to poly (adp-ribose) polymerase inhibition. J. Clin. Oncol. 2017;35:1240-1249.

    Not in our library10.1200/jco.2016.71.3677

  233. 233.

    Park P.H., Yamamoto T.M., Li H., Alcivar A.L., Xia B., Wang Y., Bernhardy A.J., Turner K.M., Kossenkov A.V., Watson Z.L., et al. Amplification of the mutation-carrying brca2 allele promotes rad51 loading and parp inhibitor resistance in the absence of reversion mutations. Mol. Cancer Ther. 2020;19:602-613.

    Not in our library10.1158/1535-7163.mct-17-0256

  234. 234.

    Noordermeer S.M., van Attikum H. Parp inhibitor resistance: A tug-of-war in brca-mutated cells. Trends Cell Biol. 2019;29:820-834.

    Not in our library10.1016/j.tcb.2019.07.008

  235. 235.
    Combined PARP and ATR inhibition potentiates genome instability and cell death in ATM-deficient cancer cells · 2020
    No notice
  236. 236.

    Jette N.R., Kumar M., Radhamani S., Arthur G., Goutam S., Yip S., Kolinsky M., Williams G.J., Bose P., Lees-Miller S.P. Atm-deficient cancers provide new opportunities for precision oncology. Cancers. 2020;12:687.

    Not in our library10.3390/cancers12030687

  237. 237.

    Gatti-Mays M.E., Karzai F.H., Soltani S.N., Zimmer A., Green J.E., Lee M.J., Trepel J.B., Yuno A., Lipkowitz S., Nair J., et al. A phase ii single arm pilot study of the chk1 inhibitor prexasertib (ly2606368) in brca wild-type, advanced triple-negative breast cancer. Oncologist. 2020;25:1013-1824.

    Not in our library10.1634/theoncologist.2020-0491

  238. 238.

    McDermott N., Buechelmaier E.S., Powell S.N. Capitalizing on cancer replication stress by preventing par chain turnover: A new type of synthetic lethality. Cancer Cell. 2019;35:344-346.

    Not in our library10.1016/j.ccell.2019.02.011

  239. 239.

    Rogers R.F., Walton M.I., Cherry D.L., Collins I., Clarke P.A., Garrett M.D., Workman P. Chk1 inhibition is synthetically lethal with loss of b-family DNA polymerase function in human lung and colorectal cancer cells. Cancer Res. 2020;80:1735-1747.

    Not in our library10.1158/0008-5472.can-19-1372

  240. 240.

    Smith H.L., Prendergast L., Curtin N.J. Exploring the synergy between parp and chk1 inhibition in matched brca2 mutant and corrected cells. Cancers. 2020;12:878.

    Not in our library10.3390/cancers12040878

  241. 241.

    Ohashi S., Kikuchi O., Nakai Y., Ida T., Saito T., Kondo Y., Yamamoto Y., Mitani Y., Nguyen Vu T.H., Fukuyama K., et al. Synthetic lethality with trifluridine/tipiracil and checkpoint kinase 1 inhibitor for esophageal squamous cell carcinoma. Mol. Cancer Ther. 2020;19:1363-1372.

    Not in our library10.1158/1535-7163.mct-19-0918

  242. 242.

    Davidovic L., Vodenicharov M., Affar E.B., Poirier G.G. Importance of poly(adp-ribose) glycohydrolase in the control of poly(adp-ribose) metabolism. Exp. Cell Res. 2001;268:7-13.

    Not in our library10.1006/excr.2001.5263

  243. 243.

    Rack J.G., Perina D., Ahel I. Macrodomains: Structure, function, evolution, and catalytic activities. Annu. Rev. Biochem. 2016;85:431-454.

    Not in our library10.1146/annurev-biochem-060815-014935

  244. 244.

    Barkauskaite E., Jankevicius G., Ladurner A.G., Ahel I., Timinszky G. The recognition and removal of cellular poly(adp-ribose) signals. FEBS J. 2013;280:3491-3507.

    Not in our library10.1111/febs.12358

  245. 245.

    Gogola E., Duarte A.A., de Ruiter J.R., Wiegant W.W., Schmid J.A., de Bruijn R., James D.I., Guerrero Llobet S., Vis D.J., Annunziato S., et al. Selective loss of parg restores parylation and counteracts parp inhibitor-mediated synthetic lethality. Cancer Cell. 2018;33:1078-1093.e1012.

    Not in our library10.1016/j.ccell.2018.05.008

  246. 246.
    DNA Replication Vulnerabilities Render Ovarian Cancer Cells Sensitive to Poly(ADP-Ribose) Glycohydrolase Inhibitors · 2019
    No notice
  247. 247.

    James D.I., Smith K.M., Jordan A.M., Fairweather E.E., Griffiths L.A., Hamilton N.S., Hitchin J.R., Hutton C.P., Jones S., Kelly P., et al. First-in-class chemical probes against poly(adp-ribose) glycohydrolase (parg) inhibit DNA repair with differential pharmacology to olaparib. ACS Chem. Biol. 2016;11:3179-3190.

    Not in our library10.1021/acschembio.6b00609

  248. 248.

    Strachan T., Read A.P., Strachan T. Human Molecular Genetics. 2011;781.

    Not in our library

  249. 249.

    Fang Y., Liao G., Yu B. Small-molecule mdm2/x inhibitors and protac degraders for cancer therapy: Advances and perspectives. Acta Pharm. Sin. B. 2020;10:1253-1278.

    Not in our library10.1016/j.apsb.2020.01.003

  250. 250.

    Couch F.B., Bansbach C.E., Driscoll R., Luzwick J.W., Glick G.G., Betous R., Carroll C.M., Jung S.Y., Qin J., Cimprich K.A., et al. Atr phosphorylates smarcal1 to prevent replication fork collapse. Genes Dev. 2013;27:1610-1623.

    Not in our library10.1101/gad.214080.113

  251. 251.

    Kwok M., Davies N., Agathanggelou A., Smith E., Oldreive C., Petermann E., Stewart G., Brown J., Lau A., Pratt G., et al. Atr inhibition induces synthetic lethality and overcomes chemoresistance in tp53- or atm-defective chronic lymphocytic leukemia cells. Blood. 2016;127:582-595.

    Not in our library10.1182/blood-2015-05-644872

  252. 252.

    Sengupta S., Linke S.P., Pedeux R., Yang Q., Farnsworth J., Garfield S.H., Valerie K., Shay J.W., Ellis N.A., Wasylyk B., et al. Blm helicase-dependent transport of p53 to sites of stalled DNA replication forks modulates homologous recombination. EMBO J. 2003;22:1210-1222.

    Not in our library10.1093/emboj/cdg114

  253. 253.
    A role for the p53 tumour suppressor in regulating the balance between homologous recombination and non-homologous end joining · 2016
    Not checked
  254. 254.
    p21 in Cancer Research · 2019
    No notice
  255. 255.

    Janyst K., Janyst M., Siernicka M., Lasek W. Synergistic antitumor effects of histone deacetylase inhibitor scriptaid and bortezomib against ovarian cancer cells. Oncol. Rep. 2018;39:1999-2005.

    Not in our library10.3892/or.2018.6248

  256. 256.

    Dong Z., Yang Y., Liu S., Lu J., Huang B., Zhang Y. Hdac inhibitor pac-320 induces g2/m cell cycle arrest and apoptosis in human prostate cancer. Oncotarget. 2018;9:512-523.

    Not in our library10.18632/oncotarget.23070

  257. 257.

    Origanti S., Cai S.R., Munir A.Z., White L.S., Piwnica-Worms H. Synthetic lethality of chk1 inhibition combined with p53 and/or p21 loss during a DNA damage response in normal and tumor cells. Oncogene. 2013;32:577-588.

    Not in our library10.1038/onc.2012.84

  258. 258.

    Xie D., Lan L., Huang K., Chen L., Xu C., Wang R., Shi Y., Wu X., Wang L., Liu Y., et al. Association of p53/p21 expression and cigarette smoking with tumor progression and poor prognosis in non-small cell lung cancer patients. Oncol. Rep. 2014;32:2517-2526.

    Not in our library10.3892/or.2014.3538

  259. 259.

    Seo Y.H., Joo Y.E., Choi S.K., Rew J.S., Park C.S., Kim S.J. Prognostic significance of p21 and p53 expression in gastric cancer. Korean J. Intern. Med. 2003;18:98-103.

    Not in our library10.3904/kjim.2003.18.2.98

  260. 260.

    Zhang M., Li J., Wang L., Tian Z., Zhang P., Xu Q., Zhang C., Wei F., Chen W. Prognostic significance of p21, p27 and survivin protein expression in patients with oral squamous cell carcinoma. Oncol Lett. 2013;6:381-386.

    Not in our library10.3892/ol.2013.1381

  261. 261.

    Galanos P., Vougas K., Walter D., Polyzos A., Maya-Mendoza A., Haagensen E.J., Kokkalis A., Roumelioti F.M., Gagos S., Tzetis M., et al. Chronic p53-independent p21 expression causes genomic instability by deregulating replication licensing. Nat. Cell Biol. 2016;18:777-789.

    Not in our library10.1038/ncb3378

  262. 262.
    Mutational signatures reveal the role of RAD52 in p53-independent p21-driven genomic instability · 2018
    Not checked
  263. 263.

    Yue X., Zhao Y., Xu Y., Zheng M., Feng Z., Hu W. Mutant p53 in cancer: Accumulation, gain-of-function, and therapy. J. Mol. Biol. 2017;429:1595-1606.

    Not in our library10.1016/j.jmb.2017.03.030

  264. 264.

    Xiao G., Lundine D., Annor G.K., Canar J., Ellison V., Polotskaia A., Donabedian P.L., Reiner T., Khramtsova G.F., Olopade O.I., et al. Gain-of-function mutant p53 r273h interacts with replicating DNA and parp1 in breast cancer. Cancer Res. 2020;80:394-405.

    Not in our library10.1158/0008-5472.can-19-1036

  265. 265.

    Duncan J.S., Whittle M.C., Nakamura K., Abell A.N., Midland A.A., Zawistowski J.S., Johnson N.L., Granger D.A., Jordan N.V., Darr D.B., et al. Dynamic reprogramming of the kinome in response to targeted mek inhibition in triple-negative breast cancer. Cell. 2012;149:307-321.

    Not in our library10.1016/j.cell.2012.02.053

  266. 266.

    Schmidlin T., Debets D.O., van Gelder C., Stecker K.E., Rontogianni S., van den Eshof B.L., Kemper K., Lips E.H., van den Biggelaar M., Peeper D.S., et al. High-throughput assessment of kinome-wide activation states. Cell Syst. 2019;9:366-374.e365.

    Not in our library10.1016/j.cels.2019.08.005

  267. 267.

    Watson N.A., Cartwright T.N., Lawless C., Camara-Donoso M., Sen O., Sako K., Hirota T., Kimura H., Higgins J.M.G. Kinase inhibition profiles as a tool to identify kinases for specific phosphorylation sites. Nat. Commun. 2020;11:1684.

    Not in our library10.1038/s41467-020-15428-0

  268. 268.

    Needham E.J., Parker B.L., Burykin T., James D.E., Humphrey S.J. Illuminating the dark phosphoproteome. Sci. Signal. 2019;12:eaau8645.

    Not in our library10.1126/scisignal.aau8645

  269. 269.

    Budayeva H.G., Kirkpatrick D.S. Monitoring protein communities and their responses to therapeutics. Nat. Rev. Drug Discov. 2020;19:414-426.

    Not in our library10.1038/s41573-020-0063-y

  270. 270.
    Phosphoproteomics of Primary Cells Reveals Druggable Kinase Signatures in Ovarian Cancer · 2017
    Not checked
  271. 271.

    Hijazi M., Smith R., Rajeeve V., Bessant C., Cutillas P.R. Reconstructing kinase network topologies from phosphoproteomics data reveals cancer-associated rewiring. Nat. Biotechnol. 2020;38:493-502.

    Not in our library10.1038/s41587-019-0391-9

  272. 272.

    Coles G.L., Cristea S., Webber J.T., Levin R.S., Moss S.M., He A., Sangodkar J., Hwang Y.C., Arand J., Drainas A.P., et al. Unbiased proteomic profiling uncovers a targetable gnas/pka/pp2a axis in small cell lung cancer stem cells. Cancer Cell. 2020;38:129-143.e7.

    Not in our library10.1016/j.ccell.2020.05.003

  273. 273.

    Lee B.Y., Hochgrafe F., Lin H.M., Castillo L., Wu J., Raftery M.J., Martin Shreeve S., Horvath L.G., Daly R.J. Phosphoproteomic profiling identifies focal adhesion kinase as a mediator of docetaxel resistance in castrate-resistant prostate cancer. Mol. Cancer Ther. 2014;13:190-201.

    Not in our library10.1158/1535-7163.mct-13-0225-t

  274. 274.

    Donnella H.J., Webber J.T., Levin R.S., Camarda R., Momcilovic O., Bayani N., Shah K.N., Korkola J.E., Shokat K.M., Goga A., et al. Kinome rewiring reveals aurka limits pi3k-pathway inhibitor efficacy in breast cancer. Nat. Chem. Biol. 2018;14:768-777.

    Not in our library10.1038/s41589-018-0081-9

  275. 275.

    Behan F.M., Iorio F., Picco G., Goncalves E., Beaver C.M., Migliardi G., Santos R., Rao Y., Sassi F., Pinnelli M., et al. Prioritization of cancer therapeutic targets using crispr-cas9 screens. Nature. 2019;568:511-516.

    Not in our library10.1038/s41586-019-1103-9

  276. 276.

    Tsherniak A., Vazquez F., Montgomery P.G., Weir B.A., Kryukov G., Cowley G.S., Gill S., Harrington W.F., Pantel S., Krill-Burger J.M., et al. Defining a cancer dependency map. Cell. 2017;170:564-576.e516.

    Not in our library10.1016/j.cell.2017.06.010

  277. 277.

    McDonald E.R., de Weck A., Schlabach M.R., Billy E., Mavrakis K.J., Hoffman G.R., Belur D., Castelletti D., Frias E., Gampa K., et al. Project drive: A compendium of cancer dependencies and synthetic lethal relationships uncovered by large-scale, deep rnai screening. Cell. 2017;170:577-592.e510.

    Not in our library10.1016/j.cell.2017.07.005

  278. 278.

    Price C., Gill S., Ho Z.V., Davidson S.M., Merkel E., McFarland J.M., Leung L., Tang A., Kost-Alimova M., Tsherniak A., et al. Genome-wide interrogation of human cancers identifies egln1 dependency in clear cell ovarian cancers. Cancer Res. 2019;79:2564-2579.

    Not in our library10.1158/0008-5472.can-18-2674

  279. 279.

    Briggs K.J., Min C., Zhang H., Huang A. Abstract 2892: Egln1 is a synthetic lethal target in arid1a-mutant ovarian cancer. Cancer Res. 2018;78:2892.

    Not in our library

  280. 280.
    Werner syndrome helicase is a selective vulnerability of microsatellite instability-high tumor cells · 2019
    No notice
  281. 281.

    Corsello S.M., Nagari R.T., Spangler R.D., Rossen J., Kocak M., Bryan J.G., Humeidi R., Peck D., Wu X., Tang A.A., et al. Discovering the anticancer potential of non-oncology drugs by systematic viability profiling. Nat. Cancer. 2020;1:235-248.

    Not in our library10.1038/s43018-019-0018-6

  282. 282.

    Nechushtan H., Hamamreh Y., Nidal S., Gotfried M., Baron A., Shalev Y.I., Nisman B., Peretz T., Peylan-Ramu N. A phase iib trial assessing the addition of disulfiram to chemotherapy for the treatment of metastatic non-small cell lung cancer. Oncologist. 2015;20:366-367.

    Not in our library10.1634/theoncologist.2014-0424

  283. 283.

    Pettersson M., Crews C.M. Proteolysis targeting chimeras (protacs)—past, present and future. Drug Discov. Today Technol. 2019;31:15-27.

    Not in our library10.1016/j.ddtec.2019.01.002

  284. 284.

    Lai A.C., Crews C.M. Induced protein degradation: An emerging drug discovery paradigm. Nat. Rev. Drug Discov. 2017;16:101-114.

    Not in our library10.1038/nrd.2016.211

  285. 285.

    Clague M.J., Heride C., Urbe S. The demographics of the ubiquitin system. Trends Cell Biol. 2015;25:417-426.

    Not in our library10.1016/j.tcb.2015.03.002

  286. 286.

    Bondeson D.P., Mares A., Smith I.E., Ko E., Campos S., Miah A.H., Mulholland K.E., Routly N., Buckley D.L., Gustafson J.L., et al. Catalytic in vivo protein knockdown by small-molecule protacs. Nat. Chem. Biol. 2015;11:611-617.

    Not in our library10.1038/nchembio.1858

  287. 287.

    Zhang X., Xu F., Tong L., Zhang T., Xie H., Lu X., Ren X., Ding K. Design and synthesis of selective degraders of egfr(l858r/t790m) mutant. Eur. J. Med. Chem. 2020;192:112199.

    Not in our library10.1016/j.ejmech.2020.112199

  288. 288.

    Burslem G.M., Smith B.E., Lai A.C., Jaime-Figueroa S., McQuaid D.C., Bondeson D.P., Toure M., Dong H., Qian Y., Wang J., et al. The advantages of targeted protein degradation over inhibition: An rtk case study. Cell Chem. Biol. 2018;25:67-77.e63.

    Not in our library10.1016/j.chembiol.2017.09.009

  289. 289.

    Jiang B., Wang E.S., Donovan K.A., Liang Y., Fischer E.S., Zhang T., Gray N.S. Development of dual and selective degraders of cyclin-dependent kinases 4 and 6. Angew. Chem. Int. Ed. Engl. 2019;58:6321-6326.

    Not in our library10.1002/anie.201901336

  290. 290.

    Brand M., Jiang B., Bauer S., Donovan K.A., Liang Y., Wang E.S., Nowak R.P., Yuan J.C., Zhang T., Kwiatkowski N., et al. Homolog-selective degradation as a strategy to probe the function of cdk6 in aml. Cell Chem. Biol. 2019;26:300-306.e309.

    Not in our library10.1016/j.chembiol.2018.11.006

  291. 291.

    Lebraud H., Wright D.J., Johnson C.N., Heightman T.D. Protein degradation by in-cell self-assembly of proteolysis targeting chimeras. ACS Cent. Sci. 2016;2:927-934.

    Not in our library10.1021/acscentsci.6b00280

  292. 292.

    Li W., Gao C., Zhao L., Yuan Z., Chen Y., Jiang Y. Phthalimide conjugations for the degradation of oncogenic pi3k. Eur. J. Med. Chem. 2018;151:237-247.

    Not in our library10.1016/j.ejmech.2018.03.066

  293. 293.

    Hines J., Gough J.D., Corson T.W., Crews C.M. Posttranslational protein knockdown coupled to receptor tyrosine kinase activation with phosphoprotacs. Proc. Natl. Acad. Sci. USA. 2013;110:8942-8947.

    Not in our library10.1073/pnas.1217206110

  294. 294.

    You I., Erickson E.C., Donovan K.A., Eleuteri N.A., Fischer E.S., Gray N.S., Toker A. Discovery of an akt degrader with prolonged inhibition of downstream signaling. Cell Chem. Biol. 2020;27:66-73.e67.

    Not in our library10.1016/j.chembiol.2019.11.014

  295. 295.

    Rana S., Bendjennat M., Kour S., King H.M., Kizhake S., Zahid M., Natarajan A. Selective degradation of cdk6 by a palbociclib based protac. Bioorg. Med. Chem. Lett. 2019;29:1375-1379.

    Not in our library10.1016/j.bmcl.2019.03.035

  296. 296.
    A Kinase-Independent Function of CDK6 Links the Cell Cycle to Tumor Angiogenesis · 2013
    Corrected
  297. 297.

    Churcher I. Protac-induced protein degradation in drug discovery: Breaking the rules or just making new ones? J. Med. Chem. 2018;61:444-452.

    Not in our library10.1021/acs.jmedchem.7b01272

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