No retraction, correction or concern found when last checked on Oct 17, 2026.

The MAPK and AMPK signalings: interplay and implication in targeted cancer therapy

Jimin Yuan, Xiaoduo Dong, Jiajun Yap and 1 more

Journal of Hematology & Oncology · 2020 · Review · CC BY

Abstract

Cancer is characterized as a complex disease caused by coordinated alterations of multiple signaling pathways. The Ras/RAF/MEK/ERK (MAPK) signaling is one of the best-defined pathways in cancer biology, and its hyperactivation is responsible for over 40% human cancer cases. To drive carcinogenesis, this signaling promotes cellular overgrowth by turning on proliferative genes, and simultaneously enables cells to overcome metabolic stress by inhibiting AMPK signaling, a key singular node of cellular metabolism. Recent studies have shown that AMPK signaling can also reversibly regulate hyperactive MAPK signaling in cancer cells by phosphorylating its key components, RAF/KSR family kinases, which affects not only carcinogenesis but also the outcomes of targeted cancer therapies against the MAPK signaling. In this review, we will summarize the current proceedings of how MAPK-AMPK signalings interplay with each other in cancer biology, as well as its implications in clinic cancer treatment with MAPK inhibition and AMPK modulators, and discuss the exploitation of combinatory therapies targeting both MAPK and AMPK as a novel therapeutic intervention.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 17, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

1The Ras/RAF/MEK/ERK (MAPK) signaling is a fundamental pathway in cell biology, and its alteration causes human cancers or developmental disorders. Given its crucial roles in physiology and pathology, this pathway has been extensively studied for over two decades. Unfortunately, the regulation of MAPK signaling remains ambiguous till now by virtue of its intrinsic complexity and diverse crosstalks with other signalings. Here, we focus on the complicated interplays between the MAPK and the AMPK signalings in cellular carcinogenesis and their implications in current targeted cancer therapies. We hope this review would provide a conceptual framework for developing more effective therapeutic approaches against hyperactive MAPK signaling-driven cancers.

The Ras/RAF/MEK/ERK (MAPK) signaling

2The Ras/RAF/MEK/ERK (MAPK, mitogen-activated protein kinase) signaling is a central pathway that regulates cellular proliferation, differentiation, and survival. This signaling pathway was discovered in the 1970s–1980s, when Ras small GTPases were identified as first oncogenes from sarcoma viruses. Later, studies on viral oncogenes had also led to the discovery of a N-terminal truncated version of RAF Ser/Thr kinase (RAF1 or CRAF). In contrast, the other two components of this signaling pathway, MEK (mitogen-activated protein kinase kinase) and ERK (mitogen-activated protein kinase) were identified as cytoplasmic protein kinases activated by mitogens in the 1990s. Following these discoveries, RAF was identified as the upstream kinase of MEK in 1992 and the first direct effector of Ras in 1993, resulting in the delineation of the whole MAPK signaling pathway, which is considered as a milestone in our understanding of how cell senses external stimuli.

3The first component of MAPK signaling, Ras small GTPases, have three gene isoforms: H-ras, K-ras, and N-ras, that encode four proteins with splicing isoforms of K-ras giving rise to K-ras4A and K-ras4B. Although all Ras proteins possess highly homologous sequences, they have quite different activities, tissue expression patterns, and effector preferences, which lead to their differential physiological and pathological functions.

4The downstream of Ras small GTPases is the RAF/MEK/ERK kinase cascade. The first kinases in this cascade, RAF/KSR (kinase suppressor of Ras) family kinases, include three RAF isoforms, i.e., CRAF, BRAF, and ARAF, and two close pseudokinases, i.e., KSR1 and KSR2. All RAF isoforms have highly homologous sequences and similar structures with three conserved regions: conserved region 1 (CR1) contains RAS-binding domain (RBD) and a Cys-rich domain; conserved region 2 (CR2) is characterized by a Ser/Thr-rich sequence; conserved region 3 (CR3) comprises of a putative kinase domain with a N-terminal acidic motif (NTA) and a C-terminal regulatory tail. Nevertheless, RAF isoforms have variable kinase activities with an order as BRAF>CRAF>ARAF likely by virtue of their distinct NTA motifs and APE motifs that contribute to the dimerization-driven transactivation of RAFs. In contrast to RAF isoforms, KSR proteins replace the RBD at the N-terminus with a coiled-coil fused sterile α-motif and Pro-rich stretch that are responsible for recruiting proteins to the plasma membrane upon stimulation, and lack the catalytic lysine in VAIK motif of kinase domain which impairs their catalytic activity. Given their associations with MEK and ERK as well as low kinase activity, KSR proteins have been thought as scaffold proteins in a long term. However, recent studies have indicated that KSR proteins can also function as allosteric activators to stimulate the catalytic activity of RAF proteins through dimerization. The side-to-side dimerization of RAF/KSR family kinases is critical not only for their activation but also for their catalytic activity towards downstream kinases. MEKs (MEK1 and MEK2) are the second kinases of the RAF/MEK/ERK kinase cascade, which have both redundant and non-redundant functions. These two dual-specific kinases comprise a short regulatory N-terminus and a canonic kinase domain. The N-terminal regulatory region of MEK1/2 contains a docking site for substrate ERKs, a nuclear export sequence that controls the cytoplasmic-nuclear shuttling of proteins, and a negative regulatory sequence that forms a helix and locks kinase in an inactive conformation. Further, through its kinase domain, MEK1/2 forms a face-to-face heterodimer with RAF/KSR, or a homodimer/heterodimer with itself, which is indispensable for its activation stimulated by RAF and for its activity towards ERKs. Like MEKs, the terminal kinases of MAPK signaling, ERKs, also include two highly homologous members, ERK1 and ERK2, which have a central kinase domain flanked by short N- and C-terminal tails. These two isoforms also have redundant functions albeit different expression patterns. However, unlike RAFs and MEKs that have very limited substrates, ERKs recognize and phosphorylate numerous substrates that include transcription factors, protein kinases and phosphatases, and other functional proteins.

5It should be noted that active Ras also turns on other signaling pathways such as PI3K/AKT/mTORC, which regulate different cellular functions. In this review, we focus only on the MAPK signaling given its dominant role in cancer biology.

Hyperactive Ras/RAF/MEK/ERK (MAPK) signaling in cancers

6The MAPK signaling plays a crucial role in cell biology and is tightly regulated in normal cells. Upon engagement of receptor tyrosine kinases (RTKs) or other stimulations, Ras small GTPases are activated by GTP/GDP exchange factors (GEFs), which in turn recruit RAF/MEK complexes to the plasma membrane and trigger the RAF/MEK/ERK kinase cascade through facilitating RAF/RAF (or KSR), RAF/MEK, and MEK/MEK interactions as well as subsequent phosphorylations. Active ERKs are further translocated into the nuclei or stay in the cytoplasm, where they phosphorylate a number of substrates that regulate cell functions. On the other hand, active MAPK signaling also turns on some negative feedback loops, which help cells return to quiescent status. An aberrant activation of MAPK signaling frequently induces human cancers or developmental disorders, though an extremely high MAPK signaling may induce cell death or senescence under some conditions.

7Hyperactive MAPK signaling exists in over 85% of cancers, which is caused directly by genetic alterations of its upstream activators or components, including RTKs, Ras, and BRAF, or indirectly by those independent of Ras or RAF, and significantly promotes disease progression. Since genetic alterations of RTKs in cancers have been extensively reviewed in recent years, here we focus on oncogenic mutations of Ras and BRAF. As a small GTPase, Ras cycles between active GTP-bound status and inactive GDP-bound status, which is regulated by GEFs and GTPase-activating proteins (GAPs). Oncogenic Ras mutations can be mainly classified into two groups: (1) mutations on glycine 12 or 13 (G12/13) that impair GAP associations and (2) mutations on glutamine 61 (Q61) that diminish the intrinsic GTPase activity of Ras, both of which lead to an extended half-life of GTP-loaded Ras. Oncogenic Ras mutations have both isoform and cancer-type preferences. K-ras is mostly mutated in all cancers (85%), followed by N-ras (12%) and H-ras (3%), and its mutations prevail in pancreatic cancers, while those of N-ras in myeloma and melanomas, and H-ras in adrenal gland cancers. This phenomenon may reflect underlying fundamental signaling landscapes, and RAS mutants interplay with these landscapes. As the downstream effector of Ras, RAF is another dominant target of oncogenic mutations in the MAPK signaling pathway. Similarly, RAF mutations have isoform preference in cancers as Ras mutations with BRAF >> CRAF > ARAF, which may arise from their different basal activities. Overall, a single point mutation that converts Val 600 into Glu in the activation loop of BRAF accounts for > 90% cases. Although BRAF (V600E) exists only in ~ 7% of all cancers, it is highly prevalent in some tissue-specific cancers such as melanoma (50~60%), thyroid cancer (40~50%), and histiocytosis (~50%), albeit the underlying molecular mechanism(s) remains unknown. In contrast to Ras and RAF, MEK and ERK have rare mutations in cancers though their mutations have been shown to be responsible for some RAF inhibitor (RAFi)-resistant cases in current cancer therapies.

Targeting the Ras/RAF/MEK/ERK (MAPK) signaling pathway for cancer therapy: promising but challenging

8Given their high prevalence in cancers, great efforts have been made to develop specific inhibitors against oncogenic Ras and RAF mutants in the last decades. These inhibitors that have been approved for clinic treatment of Ras/RAF-mutated cancers or under clinical trials are listed in Table 1. However, none of these inhibitors can effectively target the large portion of Ras mutants in cancers. Since having no attractive docking sites suitable for designing high-affinity and selective small molecule inhibitors, Ras mutants have been thought as “undruggable” cancer drivers in a long term. Until recently, a group of covalent small inhibitors that are docked into a previously unknown pocket of GDP-bound Ras and are linked to the adventive cysteine of Ras(G12C) have been developed and achieved encouraging outcomes for treating Ras(G12C)-driven cancers as a single agent in clinical trials (Fig. 1). To further enhance their efficacy, these Ras(G12C) inhibitors are also undergoing clinical evaluation when combined with SHP2 (Src homology region 2 domain-containing phosphatase-2) inhibitors that block the pathway reactivation caused by the relief of negative feedback loops (Clinical Trial: NCT04330664). In addition, these inhibitors have also been further developed into Ras(G12C) degraders by conjugating with ligands of ubiquitin E3 ligases, which effectively deplete Ras mutant proteins in cancer cells though their efficacy in vivo remains unknown. Unlike Ras(G12C), the majority of Ras mutants remain “undruggable” at present.

9It has been shown that Ras activates downstream effectors through direct interactions. Therefore, disrupting Ras/effector interactions might be an alternative approach that can effectively block cancer growth driven by Ras mutations. Such a type of small molecule blockers include rigosertib, sulindac, and MCP110, and among which, the therapeutic efficacy of rigosertib combined with nivolumab for Ras-mutated cancers is being determined by phase I/II clinical trials currently (Clinical Trial: NCT04263090). However, it has to be noted that these inhibitors impair the MAPK signaling in both Ras-mutated cancers and normal tissues and thereby their therapeutic index may not be high.

10Genetic studies have revealed that the ablation of the RAF/MEK/ERK kinase cascade but not other effector pathways is a most efficient approach to inhibit the growth of Ras-mutated cancers, which leads to extensive developments of specific inhibitors against this kinase cascade for treating Ras-mutated cancers. Moreover, these inhibitors should be also effective for treating RAF-mutated cancers. Indeed, a number of RAF/MEK/ERK inhibitors have been developed and applied to clinical trials for treating Ras/RAF-mutated cancers. At present, three RAF inhibitors and three MEK inhibitors have been approved to treat late-stage BRAF(V600E)-harboring cancers as a single agent or in combination with other chemotherapeutics and exhibited excellent efficacies (Fig. 1). However, Ras-mutated cancers possess intrinsic resistance to both RAF and MEK inhibitors, and even BRAF (V600E)-harboring cancers develop acquired resistance after 6–10 months treatment. Mechanistic studies have shown that active Ras facilitates the RAF dimerization on plasma membrane, which leads to both intrinsic and acquired resistance to RAF inhibitors. To overcome the drug resistance arising from enhanced RAF dimerization, the second-generation RAF inhibitors such as PLX8394, BGB283, TAK-580, and CCT3833 have been developed and are undergoing clinical evaluations (Clinical Trials: NCT02428712, NCT02610361, NCT03905148, NCT02327169, NCT02437227). These novel RAF inhibitors reduce the RAF dimerization-driven resistance through distinct mechanisms: (1) PLX8394 and BGB283 impair RAF dimerization upon loading on RAF proteins; (2) TAK-580 binds to and inhibits both protomers in RAF dimers; (3) CCT3833 inhibits both RAF and upstream kinases of Ras and thereby prevents the activation of Ras by the relief of negative feedback loops. Besides these second-generation RAF inhibitors, a unique RAF/MEK dual inhibitor, RO5126766, has been developed and exhibited a strong potential against both Ras- and RAF-mutated cancers in phase I clinical trials. This allosteric inhibitor docks on MEK and prevents the release of MEK from RAF as well as the subsequent phosphorylation of MEK by RAF, which gives it much more advantages than all other known RAF inhibitors according to the regulatory mechanism of the RAF/MEK/ERK kinase cascade. As to small molecule inhibitors that target the terminal kinase, ERK, although a number of them have been developed and are undergoing clinical trials, their therapeutic values for treating Ras/RAF-mutated cancers remain unknown. Like MEK inhibitors, these ERK inhibitors may not achieve a good therapeutic index as single agents by virtue of their inhibitory role in both malignant and normal tissues. However, they may contribute to anti-Ras/RAF cancer therapy as synergetic agents combined with Ras/RAF inhibitors.

11Overall, targeting hyperactive MAPK signaling has achieved exciting outcomes for treating Ras/RAF-mutated cancers. However, although some effective small molecule inhibitors have been developed and applied to clinical treatment, drug resistance and side effects remain remarkable challenges and there is still a long way to develop a long-effective approach with manageable side effects for treating Ras/RAF-mutated cancers.

12Although hyperactive MAPK signaling has a dominant role in cancer biology, it is fine-tuned by other signalings such as PI3K/AKT/mTORC and AMPK during disease progression. These signaling interplays have important impacts on both cancer progression and clinical treatment based on MAPK inhibition. In this review, we will focus on the crosstalk between MAPK and AMPK signalings.

AMPK signaling and cellular metabolism

13AMPK (AMP-activated protein kinase) is an energy sensor that monitors the AMP:ADP:ATP ratio in eukaryotic cells. This atypical protein kinase was firstly discovered as a contaminant during the purification of acetyl-CoA carboxylase (ACC), a well-studied substrate of AMPK for fatty acid (FA) synthesis nowadays (Fig. 2). However, the phosphorylation of ACC by AMPK in response to the high AMP/ATP ratio had not been revealed until a decade later, and the enzyme was thus named as AMPK thereafter (Fig. 2). Biochemical studies have shown that AMPK consists of three subunits including the catalytic α subunit and the regulatory β and γ subunits (Fig. 2). In mammals, AMPK subunits are encoded as several isoforms (α1, α2; β1, β2; γ1, γ2, γ3), which are preferentially expressed in specific tissues or organisms. For instance, the α2 subunit associates only with β1 in type I muscle fibers, while it binds to both β1 and β2 in type II muscle fibers. Also, the liver formulation of AMPK subunits differs among species as that α1β2γ1 is dominant in human whereas α1β1γ1 and α2β1γ1 in dog and rat, respectively. Although an isoform replacement of AMPK subunits may not extensively affect the basal activity of AMPK as adaptive responses such as exercise do, it alters AMPK’s subcellular locations and sensitivity as well as interactions with other signaling pathways. The organism/tissue/stage-specific selectivity of subunit isoforms complicates AMPK’s regulation.

14As a key sensor of cellular energy stress, the activity of AMPK is predominantly regulated by cellular AMP/ADP/ATP that competitively binds to the γ subunit of AMPK and thus promotes or inhibits the phosphorylation of Thr172 on α subunit by the tumor suppressor liver kinase B1 (LKB1) or the dephosphorylation of this site by phosphatases (Fig. 2). Besides adenine nucleotides, intracellular calcium ions activate AMPK through calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2, also called CAMKKβ) (Fig. 2), which acts downstream of the hormone-activated receptors such as muscarinic receptors and ghrelin receptor on endothelial cells or neuron cells. On the other hand, AMPK can be inhibited by a metabolite of glucose, fructose 1,6-bisphosphate (FBP), which binds to the aldolase and prevents the interaction of AMPK with LKB1 in glucose-rich environments (Fig. 2). Active AMPK has more than 100 downstream substrates that regulate the metabolism of lipids, cholesterol, carbohydrates, and amino acids.

15Active AMPK promotes the oxidation of fatty acids and inhibits the synthesis of fatty acids and cholesterol, which involves largely in acetyl-CoA. AMPK phosphorylates and inhibits HMG-CoA reductase (HMGR) that requires acetyl-CoA in its reduction reaction (Fig. 2). Also, AMPK phosphorylates ACC that converts acetyl-CoA to malonyl-CoA and therefore slows down the de novo fatty acid (FA) synthesis and increases the FA oxidation (Fig. 2). Alternatively, AMPK regulates the lipid metabolism through altering the mitochondria structure and function. In the mitochondria, AMPK phosphorylates A-kinase anchoring protein 1 (AKAP1), a key scaffold protein for protein kinase A (PKA), and facilitates the phosphorylation of a mitochondria fusion factor, dynamin-related protein 1 (DRP1) by PKA, which promotes mitochondrial fusion and oxidative phosphorylation. Moreover, AMPK accelerates the mitochondria biogenesis likely through phosphorylating and activating the transcriptional activator, proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) (Fig. 2). However, upon energy stress, AMPK plays an opposite role in mitochondria biology. Under this condition, AMPK is essential for the fragmentation of mitochondria. AMPK phosphorylates mitochondrial fission factor (MFF) on Ser129 and thereby facilitates the translocation of DRP1 from cytosol to mitochondria membrane in energy stress-driven mitochondria fission. Then, AMPK promotes the clearance of damaged mitochondria through autophagy. In this process, AMPK binds directly to and phosphorylates the unc-51-like autophagy activating kinase 1 (ULK1), Autophagy-related gene 9 (ATG9), and Beclin 1, which triggers the autophagosome formation (Fig. 2).

16Active AMPK directly regulates the carbohydrate metabolism or indirectly through altering the fatty acid metabolism as described above. Activation of AMPK stimulates the expression and plasma membrane translocation of solute carrier family member (GLUT) proteins and thereby facilitates glucose import (Fig. 2). Intracellularly, AMPK phosphorylates and activates 6-phosphofructo-2-kinase (PFK2) that is responsible for the synthesis of fructose 2,6-bisphosphate, a potent stimulator of glycolysis, and thus accelerates glycolysis (Fig. 2). Furthermore, AMPK appears to phosphorylate and inhibit glycogen synthase in the liver, which dampens glycogen synthesis and thus indirectly enhances glycolysis.

17Active AMPK maintains cellular amino acid homeostasis mainly by controlling the activity of mammalian target of rapamycin complex 1 (mTORC1). The mTORC1 is a central sensor of cellular amino acids that samples amino acids in both cytosol and lysosome. Upon activation by amino acids, mTORC1 stimulates protein synthesis by phosphorylating ribosomal protein S6 kinase B1 (S6K) and eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), which enhances the consumption of cellular amino acids. Moreover, active mTORC1 blocks cellular autophagy by phosphorylating ULK1 and impairs the recycling of amino acids. Both effects of mTORC1 lead to a remarkable drop of cellular amino acid reservoir. Active AMPK has been shown to inhibit the activity of mTORC1 direct and indirectly upon energy stress, which limits the expenditure of amino acids. Alternatively, active AMPK can restrict protein synthesis by phosphorylating and thereby inhibiting eukaryotic translation elongation factor 2 (eEF2) kinase, a key regulator of protein synthesis. To restore cellular amino acid reservoir, active AMPK stimulates cellular autophagy as discussed above, which degrades surplus or dysfunctional proteins into amino acids. In addition, it is worth noted that cellular amino acids can affect the activity of AMPK reversely. Dependent on conditions/contexts, either amino acids may inhibit or stimulate the activity of AMPK though underlying molecular mechanisms remain ambiguous.

AMPK signaling in cancer biology

18It is well known that AMPK is a putative substrate of tumor suppressor, LKB1 (Fig. 2). Therefore, AMPK has been generally considered as a key effector that mediates the tumor-suppressive function of LKB1. Indeed, a genetic ablation of the AMPK α subunit in mice accelerates Myc-driven lymphomagenesis through facilitating a metabolic shift to aerobic glycolysis. Simultaneously, AMPK inhibitors (AMPKi) promote epithelial-to-mesenchymal transition (EMT) in breast and prostate cancers. These studies validate AMPK as a tumor suppressor under certain circumstances. Further mechanistic studies have demonstrated that AMPK prevents cancers through phosphorylating multiple targets that play indispensable roles on different layers of disease progression. AMPK phosphorylates angiomotin like 1 (AMOTL1), an adaptor protein in the Hippo-Yap pathway, and thus blocks Yes1 associated transcriptional regulator (YAP) activity, which impairs cancer cells’ proliferation and survival. AMPK also phosphorylates TSC complex subunit 2 (TSC2) and regulatory associated protein of MTOR complex 1 (Raptor) and thereby inactivates mTORC1, which in turn elevates cellular autophagy activity and inhibits cancer initiation. To bypass this inhibitory effect, cancer cells can activate the MAGE family member A 3/6 (MAGEA3/6)-tripartite motif containing 28 (TRIM28) ubiquitin ligase complex that targets the AMPK α subunit for degradation and thus re-activates mTORC1 to restrict cellular autophagy. Moreover, AMPK is able to phosphorylate enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) and thereby disrupts the polycomb repressive complex 2 (PRC2), which relieves the epigenetic silence of tumor suppressors in cancers. Alternatively, AMPK phosphorylates and stabilizes another epigenetic master regulator, Tet methylcytosine dioxygenase 2 (TET2), which functions as a putative tumor suppressor to prevent tumorigenesis. Altogether, these findings indicate that AMPK has a pronounced anti-tumor activity as its upstream kinase, LKB1 does.

19Although significant studies have shown that AMPK dampens the pathogenesis of cancers, some emerging findings indicate that it may promote disease progression under other circumstances. In T cell acute lymphoblastic leukemia (T-ALL), oncogenic Notch signaling induces a high level of aerobic glycolysis which needs to be restrained by AMPK, and loss of AMPK results in energy stress-driven apoptosis of leukemic cells and slows down disease progression. Similarly, in acute myeloid leukemia (AML), metabolic stress elevates the ROS level and induces DNA damage in leukemia-initiating cells (LICs), and AMPK confers metabolic stress resistance to LICs. AMPK knockout or pharmaceutical inhibition under metabolic stress kills LICs and inhibits leukemogenesis. Moreover, AMPK plays a determinant role in maintaining the NADPH homeostasis in cancer cells upon energy stress, which is critical for cancer cell survival. Depletion of the AMPK α subunit or its upstream kinase, LKB1 makes cancer cells susceptible to death upon energy stress, such as glucose limitations, anchorage-independent growth, and solid tumor formation in vivo. In KrasG12D-driven non-small cell lung cancer, the failure of AMPK activation by virtue of LKB1 mutation sensitizes cancer cells for phenformin-induced metabolic stress, further supporting that AMPK adapts cancer cells for metabolic stress. Alternatively, a synthetic lethal screening has revealed that AMPK activation by AMPK-related kinase 5 (ARK5) is essential for Myc-driven cancer progression. Consistent with this finding, AMPK has been shown to promote survival of Myc-positive melanoma cells with N-Ras mutation by restraining oxidative stress. In addition, AMPK sustains the activation of oncogenic protein kinase B (AKT) signaling upon stress or epidermal growth factor receptor (EGFR) engagement in breast cancers. Besides these direct effects on cancer cells, AMPK may promote cancer progression by altering the cancer microenvironment. AMPK signaling has been shown to intrinsically promote the immunoregulatory activity of myeloid-derived suppressor cells (MDSC), which dysfunctions T cells in cancer tissue. All these findings indicate that AMPK can significantly contribute to the disease progression of variable cancers via distinct manners.

20Unlike LKB1, which is frequently mutated or deleted in cancer genomes, AMPK has nearly no mutations, and on the contrary, is upregulated in some types of cancers such as glioblastoma, suggesting that it may play a paradoxical role in carcinogenesis. Dependent on origins of cancers, driver mutations, developmental stages, and external conditions, AMPK may dampen or promote the disease progression of cancers, and uncovering underlying mechanisms would propel cancer therapy development by targeting this signaling pathway.

The crosstalk between MAPK and AMPK signalings

21As described above, the MAPK signaling controls cellular proliferation, differentiation, and survival, whereas the AMPK signaling regulates cellular metabolism. However, many studies have indicated that these two distinct signalings have profound and complicated interplays in both physiological and pathological processes. In quiescent cells, the AMPK signaling maintains energy homeostasis by switching on catabolic pathways that generate ATP, while switching off anabolic pathways that are required for cell growth. Upon mitogen stimulation, the MAPK signaling is turned on and drives cellular proliferation/differentiation, which needs cells shifting their metabolic program from catabolic to anabolic for biomass synthesis. To achieve this, the MAPK signaling activates transcription factors such as Myc and Hypoxia inducible factor 1 subunit alpha (HIF-1α), which control the expression of glycolytic enzymes and promote aerobic glycolysis. Furthermore, the MAPK signaling directly regulates AMPK signaling and thus constrains the AMPK signaling-driven oxidative phosphorylation of biomaterials. These interplays frequently occur with marginal coordination when cells response to different stimuli such as oncogenesis and cell stress. Recent studies have revealed that the MAPK signaling regulates AMPK signaling on different layers under distinct circumstances. Firstly, ERK and ribosomal protein S6 kinase A (RSK), two downstream kinases of MAPK signaling, have been shown to phosphorylate and inhibit the upstream activator of AMPK, LKB1, and thereby block the activation of AMPK by LKB1 in BRAF(V600E)-driven melanoma (Fig. 3a). Secondly, ERK likely phosphorylates the α subunit of AMPK directly on negative regulatory sites Ser485/491 and impairs its catalytic activity, which is essential for C-C motif chemokine receptor 7 (CCR7)-dependent survival of mature dendritic cells. Thirdly, KSR, one of the key components of MAPK module, has been shown to interact with all AMPK subunits and regulate the AMPK-dependent energy expenditure (Fig. 3b). In addition, the MAPK signaling controls the subcellular localization of AMPK and thus alters its function under cell stress. All these findings suggest that AMPK could function as a downstream effector of MAPK signaling.

22The interplays between MAPK and AMPK signalings are binary, and the AMPK signaling can regulate MAPK signaling reversely. Conclusive evidence shows that AMPK can directly phosphorylate the RAF/KSR family kinases, the pivotal components of MAPK module, and alter their activities under variable conditions. It is well established that the hetero-/homo-dimerization of RAF/KSR family kinases plays a determinant role in the activation of MAPK signaling, which requires the association of 14-3-3, a dimeric scaffold protein with their carboxyl-terminus. Mechanistic studies have revealed that a 14-3-3 dimer associates with the C-terminus of two individual RAF/KSR molecules and facilitates their dimerization and subsequent activation (Fig. 4a). Since RAF/KSR family kinases have the other conserved 14-3-3 binding site at the N-terminus, however, if a 14-3-3 dimer binds to the N- and C-terminus of a single RAF/KSR intramolecularly, it will stabilize RAF/KSR in an autoinhibitory conformation and thus prevent the dimerization-driven activation of kinases (Fig. 4b). AMPK has been shown to phosphorylate the C-terminal 14-3-3 binding site of RAF/KSR family kinases and promote the intra- or inter-molecular 14-3-3 associations with these kinases respectively (Fig. 4). Among RAF/KSR family kinases, CRAF is the first member that has been shown being phosphorylated by AMPK on its C-terminal 14-3-3 binding site. AMPKi by pharmaceutical inhibitors abolishes the dimer-dependent paradoxical activation of MAPK signaling driven by the RAF inhibitors in Ras-mutated cancers, suggesting that AMPK-mediated phosphorylation of the C-terminal 14-3-3 binding site on CRAF promotes the intermolecular association of 14-3-3 dimers with CRAF homo- or hetero-dimers (Fig. 4a). This molecular mechanism may also be responsible for the hyperactive MAPK signaling induced by metabolic stress in Ras-mutated melanoma. Upon metabolic perturbations, AMPK is activated in this type of melanoma cells and promotes KSR/CRAF heterodimerization likely through altering 14-3-3 binding manners, which leads to a highly activated MAPK signaling. Besides CRAF and KSR, the association of BRAF with 14-3-3 is also regulated by AMPK-mediated phosphorylation. In BRAF(V600E)-harboring melanoma, metabolic stress-activated AMPK phosphorylates the C-terminal 14-3-3 binding site of BRAF and promotes the intramolecular association of a single BRAF molecule with a 14-3-3 dimer, which breaks the BRAF/KSR heterodimer and thus inhibits MAPK signaling, although whether active AMPK phosphorylates the N-terminal 14-3-3 binding site of BRAF under this condition needs further investigation (Fig. 4b). Consistent with these findings, AMPK activators have been shown to inhibit the proliferation of BRAF(V600E)-harboring melanoma and enhance the therapeutic efficacy of BRAF inhibitors on this type of melanoma. Over all, the distinct regulations of RAF/KSR family kinases by AMPK lead to completely different outputs of MAPK signaling, which determine cell fates under variable conditions.

23The interplays between MAPK and AMPK signalings also alter cellular autophagy, particularly that of cancer cells. Cancer cells with Ras/RAF mutations have much higher activity of autophagy, which significantly contributes to disease progression, although how autophagy is upregulated in these cancer cells remains unknown. Elevated autophagy in Ras/RAF-mutated cancer cells preserves mitochondrial and glycolytic functions by recycling dysfunctional mitochondria. Disruption of autophagy by depleting Atg7 or Atg5 induces cellular senescence and reduces cancer burden in these diseases. The critical role of autophagy in K-ras-driven cancers is further confirmed by a synthetic lethal screening for factors that support K-ras addiction, which identified Atg7 and RAF kinases as a minimal oncoeffector combination that best discriminates K-ras cancer cells from normal cells. It is well known that AMPK is a prominent regulator of autophagy in spite of its key role as an energy sensor, which drives cellular autophagy machinery via the LKB1/AMPK/ULK1 axis. Since LKB1 is inhibited by hyperactive MAPK signaling, this signal axis should not be responsible for elevated activity of autophagy in Ras/RAF-driven cancers. However, it provides cancer cells a protective strategy for adapting themselves to MAPK inhibition. Indeed, MAPK inhibition (MAPKi) by RAF/MEK/ERK inhibitors in Ras/RAF-mutated cancer cells further elevates autophagic flux through AMPK, which restores cellular metabolic hemostasis and leads to tolerance towards MAPKi.

Combinatorial targeting of MAPK and AMPK signalings to treat Ras/RAF-mutated cancers

24Hyperactive MAPK signaling is responsible for a large portion of cancers, and genetic alterations that aberrantly activate this pathway mainly occur on receptor tyrosine kinases (RTKs), Ras small GTPases, and BRAF. In current cancer therapies, hyperactive RTKs can be effectively targeted by tyrosine kinase inhibitors (TKIs) or neutralizing antibodies, while there are no drugs that are able to specifically target most Ras mutants. To treat Ras/BRAF-mutated cancers, RAF/MEK inhibitors such as vemurafenib, dabrafenib, encorafenib, trametinib, cobimetinib, and binimetinib have been developed and applied to disease management. These inhibitors have exhibited a promising efficacy towards most BRAF-mutated cancers (Fig. 5). In contrast, Ras-mutated cancers are intrinsically resistant to these drugs, which do not inhibit but paradoxically activate the MAPK signaling through promoting RAF family kinases’ dimerization. Furthermore, even BRAF-mutated cancers develop adaptive resistance to these drugs after 6~10 months treatment by either activating Ras or alternatively splicing BRAF mutant. Therefore, for most cases, once cancer cells possess high Ras activity, these drugs lose their efficacy as a monotherapy. To improve the efficacy of MAPKi against Ras/RAF-mutated cancers, emerging evidence indicates that disruption of MAPK signaling complex, particularly dimerization of RAF family kinases, and/or synergistic targeting of synthetic lethality of MAPK signaling should be two feasible strategies, both of which are involved in AMPK signaling.

25It has been shown that the components of MAPK signaling form a super complex in cancer cells with active Ras, which leads to resistance towards MAPKi. Assembly of this complex involves in RAF/RAF (or KSR), RAF (or KSR)/MEK, MEK/MEK, as well as RAF (or KSR)/14-3-3 interactions, and disruption of these interactions contributes to an effective inhibition of MAPK signaling. As discussed above, AMPK directly regulates RAF (or KSR)/14-3-3 interaction by phosphorylating the 14-3-3 binding sites on RAF (or KSR) and thus facilitates or impairs RAF/RAF (or KSR) dimerization. In Ras-mutated cancer cells or RAFi-resistant cancer cells with active Ras, CRAF is the key isoform of RAF family kinases responsible for disease progression and drug resistance, whose phosphorylation on the C-terminal 14-3-3 binding site by AMPK plays a determinant role in the paradoxical effect of RAF inhibitors, and AMPKi sensitizes these cancer cells to RAF inhibitors both in vitro and in vivo (Wang & Hu, unpublished data) (Fig. 4b). Although the components of MAPK signaling do not assemble a super complex in BRAF-mutated cancer cells, constitutively active BRAF mutant still functions as homo- or hetero-dimers (BRAF/BRAF or BRAF/KSR) that can be disrupted by AMPK-driven phosphorylation of both N- and C-terminal 14-3-3 binding sites. In this type of cancers, AMPK activators have been shown to significantly enhance the therapeutic efficacy of RAF inhibitors. Taken together, altering RAF/KSR dimerization by using either AMPK inhibitors or activators may remarkably improve the targeted therapies of Ras/RAF-mutated cancers with RAF inhibitors.

26Since most oncogenic Ras mutants are undruggable, efforts for developing effective approaches against Ras-mutated cancers have been switched to identify and target synthetic lethal vulnerabilities of Ras mutants over decades, which led to the discovery of some putative factors essential for in vitro growth of Ras-mutated cancer cells. Unfortunately, most factors except those regulating cellular autophagy exhibit little-to-no therapeutic values for treating Ras-mutated cancers in vivo so far. As we know, Ras/RAF-mutated cancer cells have a high basal activity of autophagy though hyperactive MAPK signaling inhibits the LKB1-AMPK-ULK1 signaling axis, which is critical for maintaining cellular metabolic homeostasis. MAPKi relives the LKB1-AMPK-ULK1 axis and thus further elevates autophagic flux in Ras/RAF-mutated cancer cells, which adapts Ras-mutated cancer cells to MAPKi, or promotes drug tolerance and subsequent resistance of RAF-mutated cancer cells (Fig. 5). Pharmaceutical blocking of AMPK by compound C has been shown to remarkably reduce the RAFi-resistant clones arising from BRAF-mutated melanoma. Furthermore, combinations of autophagy inhibitors with RAF/MEK/ERK inhibitors (chloroquine plus vemurafenib, hydroxychloroquine plus trametinib, or chloroquine plus SCH772984) can effectively block the growth of K-ras-mutated pancreatic ductal adenocarcinoma, N-ras-mutated melamona, as well as BRAF-mutated colorectal cancer and melanoma in vivo (Fig. 5). However, it has to be noted that although both AMPK inhibitors and activators may synergistically enhance the therapeutic efficacy of RAF inhibitors against BRAF-mutated cancers, molecular mechanisms underlying these phenomena are completely different.

27Combinatorial inhibition of both MAPK and AMPK signalings has shown promising potentials for treating Ras/RAF-mutated cancers. To target MAPK signaling, the first-generation RAF/MEK/ERK inhibitors have been developed and applied to clinic treatment, and the second-generation drugs that can inhibit RAF mutants with elevated dimer affinity or have much less paradoxical effect have also undergone clinical trials. In contrast, the drug development of AMPK-specific activators and inhibitors lags far behind the needs for treating cancers, though some AMPK activators such as O304 are undergoing clinical trials for other diseases. Currently, only two non-specific AMPK activators, phenformin and metformin, that have been approved for treating type II diabetes are undergoing clinic evaluations as combinatorial agents for treating BRAF-mutated melanoma together with vemurafenib or dabrafenib/trametinib. As to AMPK-specific inhibitors, only compound C has been tested in animal models at present. Although a combination of compound C with RAF inhibitor, vemurafenib can effectively inhibit the growth of Ras-mutated cancer cells in vitro, and its therapeutic efficacy/benefit needs further investigations by using preclinical animal models and through clinical trials. Overall, these unmet needs for AMPK-specific activators and inhibitors in targeted cancer therapies appeal to accelerate their pharmaceutical development.

Conclusions and perspectives

28Recent studies have provided compelling evidence that interplays between MAPK and AMPK signalings play a critical role in cell physiology and have important implications in disease treatment, particularly for cancer. Combinatory targeting both MAPK and AMPK signalings represents for a promising therapeutic intervention. However, although the framework by which these two signalings interact with each other has been illustrated, the precise molecular basis and their impacts on cancer therapies remain largely unresolved. For instance, how the AMPK signaling differentially regulates the dimerization of different RAF isoforms (BRAF versus CRAF) and thus distinctly alters the outputs of MAPK signaling in Ras- versus RAF-mutated cancers is unclear. Besides elevating autophagic flux, does the AMPK signaling plays other roles in the MAPKi-resistance of Ras/RAF-mutated cancers? Addressing these questions would deepen our understanding of MAPK/AMPK interplays and help us develop better combinatorial therapies for cancers and other diseases. In addition, developing AMPK-specific activators/inhibitors would be an attractive research topic for both academy and pharmaceutical industry in the next years given their absence and unmet needs in clinic treatment.

References 283

1.
Rapp UR, Todaro C. Generation of new mouse sarcoma viruses in cell culture. Science. 1978;201(4358):821-824.
Not in our library10.1126/science.210501
2.
Jansen HW, Lurz R, Bister K, Bonner TI, Mark GE, Rapp UR. Homologous cell-derived oncogenes in avian carcinoma virus MH2 and murine sarcoma virus 3611. Nature. 1984;307(5948):281-284.
Not in our library10.1038/307281a0
3.
Jansen HW, Ruckert B, Lurz R, Bister K. Two unrelated cell-derived sequences in the genome of avian leukemia and carcinoma inducing retrovirus MH2. EMBO J. 1983;2(11):1969-1975.
Not in our library10.1002/j.1460-2075.1983.tb01686.x
4.
Bonner T, O'Brien SJ, Nash WG, Rapp UR, Morton CC, Leder P. The human homologs of the raf (mil) oncogene are located on human chromosomes 3 and 4. Science. 1984;223(4631):71-74.
Not in our library10.1126/science.6691137
5.
Kozak C, Gunnell MA, Rapp UR. A new oncogene, c-raf, is located on mouse chromosome 6. J Virol. 1984;49(1):297-299.
Not in our library10.1128/jvi.49.1.297-299.1984
6.
Bonner TI, Kerby SB, Sutrave P, Gunnell MA, Mark G, Rapp UR. Structure and biological activity of human homologs of the raf/mil oncogene. Mol Cell Biol. 1985;5(6):1400-1407.
Not in our library10.1128/mcb.5.6.1400-1407.1985
7.
Ahn NG, Weiel JE, Chan CP, Krebs EG. Identification of multiple epidermal growth factor-stimulated protein serine/threonine kinases from Swiss 3T3 cells. J Biol Chem. 1990;265(20):11487-11494.
Not in our library
8.
Ray LB, Sturgill TW. Characterization of insulin-stimulated microtubule-associated protein kinase. Rapid isolation and stabilization of a novel serine/threonine kinase from 3T3-L1 cells. J Biol Chem. 1988;263(25):12721-12727.
Not in our library
9.
Rossomando AJ, Payne DM, Weber MJ, Sturgill TW. Evidence that pp42, a major tyrosine kinase target protein, is a mitogen-activated serine/threonine protein kinase. Proc Natl Acad Sci U S A. 1989;86(18):6940-6943.
Not in our library10.1073/pnas.86.18.6940
10.
Boulton TG, Nye SH, Robbins DJ, Ip NY, Radzlejewska E, Morgenbesser SD, et al. ERKs: a family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF. Cell. 1991;65(4):663-675.
Not in our library10.1016/0092-8674(91)90098-j
11.
Crews CM, Erikson RL. Purification of a murine protein-tyrosine/threonine kinase that phosphorylates and activates the Erk-1 gene product: relationship to the fission yeast byr1 gene product. Proc Natl Acad Sci U S A. 1992;89(17):8205-8209.
Not in our library10.1073/pnas.89.17.8205
12.
Rapp UR, Goldsborough MD, Mark GE, Bonner TI, Groffen J, Reynolds FH, et al. Structure and biological activity of v-raf, a unique oncogene transduced by a retrovirus. Proc Natl Acad Sci U S A. 1983;80(14):4218-4222.
Not in our library10.1073/pnas.80.14.4218
13.
Moelling K, Heimann B, Beimling P, Rapp UR, Sander T. Serine- and threonine-specific protein kinase activities of purified gag-mil and gag-raf proteins. Nature. 1984;312(5994):558-561.
Not in our library10.1038/312558a0
14.
Cox AD, Der CJ. Ras history: the saga continues. Small GTPases. 2010;1(1):2-27.
Not in our library10.4161/sgtp.1.1.12178
15.
Ehrenreiter K, Piazzolla D, Velamoor V, Sobczak I, Small JV, Takeda J, et al. Raf-1 regulates Rho signaling and cell migration. J Cell Biol. 2005;168(6):955-964.
Not in our library10.1083/jcb.200409162
16.
Rubiolo C, Piazzolla D, Meissl K, Beug H, Huber JC, Kolbus A, et al. A balance between Raf-1 and Fas expression sets the pace of erythroid differentiation. Blood. 2006;108(1):152-159.
Not in our library10.1182/blood-2005-09-3866
17.
Kolbus A, Pilat S, Husak Z, Deiner EM, Stengl G, Beug H, et al. Raf-1 antagonizes erythroid differentiation by restraining caspase activation. J Exp Med. 2002;196(10):1347-1353.
Not in our library10.1084/jem.20020562
18.
Kolch W, Heidecker G, Lloyd P, Rapp UR. Raf-1 protein kinase is required for growth of induced NIH/3T3 cells. Nature. 1991;349(6308):426-428.
Not in our library10.1038/349426a0
19.
Daum G, Eisenmann-Tappe I, Fries HW, Troppmair J, Rapp UR. The ins and outs of Raf kinases. Trends Biochem Sci. 1994;19(11):474-480.
Not in our library10.1016/0968-0004(94)90133-3
20.
Fischer A, Hekman M, Kuhlmann J, Rubio I, Wiese S, Rapp UR. B- and C-RAF display essential differences in their binding to Ras: the isotype-specific N terminus of B-RAF facilitates Ras binding. J Biol Chem. 2007;282(36):26503-26516.
Not in our library10.1074/jbc.m607458200
21.
Diaz B, Barnard D, Filson A, MacDonald S, King A, Marshall M. Phosphorylation of Raf-1 serine 338-serine 339 is an essential regulatory event for Ras-dependent activation and biological signaling. Mol Cell Biol. 1997;17(8):4509-4516.
Not in our library10.1128/mcb.17.8.4509
22.
Mason CS, Springer CJ, Cooper RG, Superti-Furga G, Marshall CJ, Marais R. Serine and tyrosine phosphorylations cooperate in Raf-1, but not B-Raf activation. EMBO J. 1999;18(8):2137-2148.
Not in our library10.1093/emboj/18.8.2137
23.
Kohler M, Brummer T. B-Raf activation loop phosphorylation revisited. Cell Cycle. 2016;15(9):1171-1173.
Not in our library10.1080/15384101.2016.1159111
24.
Dhillon AS, Yip YY, Grindlay GJ, Pakay JL, Dangers M, Hillmann M, et al. The C-terminus of Raf-1 acts as a 14-3-3-dependent activation switch. Cell Signal. 2009;21(11):1645-1651.
Not in our library10.1016/j.cellsig.2009.07.001
25.
Kondo Y, Ognjenovic J, Banerjee S, Karandur D, Merk A, Kulhanek K, et al. Cryo-EM structure of a dimeric B-Raf:14-3-3 complex reveals asymmetry in the active sites of B-Raf kinases. Science. 2019;366(6461):109-115.
Not in our library10.1126/science.aay0543
26.
Hobbs GA, Der CJ. RAS mutations are not created equal. Cancer Discov. 2019;9(6):696-698.
Not in our library10.1158/2159-8290.cd-19-0406
27.
Hu J, Stites EC, Yu H, Germino EA, Meharena HS, Stork PJS, et al. Allosteric activation of functionally asymmetric RAF kinase dimers. Cell. 2013;154(5):1036-1046.
Not in our library10.1016/j.cell.2013.07.046
28.
Yuan J, Ng WH, Lam PYP, Wang Y, Xia H, Yap J, et al. The dimer-dependent catalytic activity of RAF family kinases is revealed through characterizing their oncogenic mutants. Oncogene. 2018;37(43):5719-5734.
Not in our library10.1038/s41388-018-0365-2
29.
Huleihel M, Goldsborough M, Cleveland J, Gunnell M, Bonner T, Rapp UR. Characterization of murine A-raf, a new oncogene related to the v-raf oncogene. Mol Cell Biol. 1986;6(7):2655-2662.
Not in our library10.1128/mcb.6.7.2655-2662.1986
30.
Beck TW, Huleihel M, Gunnell M, Bonner TI, Rapp UR. The complete coding sequence of the human A-raf-1 oncogene and transforming activity of a human A-raf carrying retrovirus. Nucleic Acids Res. 1987;15(2):595-609.
Not in our library10.1093/nar/15.2.595
31.
Therrien M, Chang HC, Solomon NM, Karim FD, Wassarman DA, Rubin GM. KSR, a novel protein kinase required for RAS signal transduction. Cell. 1995;83(6):879-888.
Not in our library10.1016/0092-8674(95)90204-x
32.
Rajakulendran T, Sahmi M, Lefrancois M, Sicheri F, Therrien M. A dimerization-dependent mechanism drives RAF catalytic activation. Nature. 2009;461(7263):542-545.
Not in our library10.1038/nature08314
33.
Hu J, Yu H, Kornev AP, Zhao J, Filbert EL, Taylor SS, et al. Mutation that blocks ATP binding creates a pseudokinase stabilizing the scaffolding function of kinase suppressor of Ras, CRAF and BRAF. Proc Natl Acad Sci U S A. 2011;108(15):6067-6072.
Not in our library10.1073/pnas.1102554108
34.
Hu J, Ahuja LG, Meharena HS, Kannan N, Kornev AP, Taylor SS, et al. Kinase regulation by hydrophobic spine assembly in cancer. Mol Cell Biol. 2015;35(1):264-276.
Not in our library10.1128/mcb.00943-14
35.
Shaw AS, Kornev AP, Hu J, Ahuja LG, Taylor SS. Kinases and pseudokinases: lessons from RAF. Mol Cell Biol. 2014;34(9):1538-1546.
Not in our library10.1128/mcb.00057-14
36.
Taylor SS, Shaw A, Hu J, Meharena HS, Kornev A. Pseudokinases from a structural perspective. Biochem Soc Trans. 2013;41(4):981-986.
Not in our library10.1042/bst20130120
37.
Yap J, Yuan J, Tee ZH, Huang X, Ng WH, Hu J. Characterize disease-related mutants of RAF family kinases by using a set of practical and feasible methods. J Vis Exp. 2019;(149). 10.3791/59795.
Not in our library10.3791/59795
38.
Park E, Rawson S, Li K, Kim BW, Ficarro SB, Pino GG, et al. Architecture of autoinhibited and active BRAF-MEK1-14-3-3 complexes. Nature. 2019;575(7783):545-550.
Not in our library10.1038/s41586-019-1660-y
39.
Varga A, Ehrenreiter K, Aschenbrenner B, Kocieniewski P, Kochanczyk M, Lipniacki T, et al. RAF1/BRAF dimerization integrates the signal from RAS to ERK and ROKalpha. Sci Signal. 2017;10(469):eaai8482.
Not in our library10.1126/scisignal.aai8482
40.
Weber CK, Slupsky JR, Kalmes HA, Rapp UR. Active Ras induces heterodimerization of cRaf and BRaf. Cancer Res. 2001;61(9):3595-3598.
Not in our library
41.
Rushworth LK, Hindley AD, O'Neill E, Kolch W. Regulation and role of Raf-1/B-Raf heterodimerization. Mol Cell Biol. 2006;26(6):2262-2272.
Not in our library10.1128/mcb.26.6.2262-2272.2006
42.
Baljuls A, Mahr R, Schwarzenau I, Muller T, Polzien L, Hekman M, et al. Single substitution within the RKTR motif impairs kinase activity but promotes dimerization of RAF kinase. J Biol Chem. 2011;286(18):16491-16503.
Not in our library10.1074/jbc.m110.194167
43.
Kyriakis JM, App H, Zhang XF, Banerjee P, Brautigan DL, Rapp UR, et al. Raf-1 activates MAP kinase-kinase. Nature. 1992;358(6385):417-421.
Not in our library10.1038/358417a0
44.
Alessi DR, Saito Y, Campbell DG, Cohen P, Sithanandam G, Rapp U, et al. Identification of the sites in MAP kinase kinase-1 phosphorylated by p74raf-1. EMBO J. 1994;13(7):1610-1619.
Not in our library10.1002/j.1460-2075.1994.tb06424.x
45.
Ohren JF, Chen H, Pavlovsky A, Whitehead C, Zhang E, Kuffa P, et al. Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition. Nat Struct Mol Biol. 2004;11(12):1192-1197.
Not in our library10.1038/nsmb859
46.
Yuan J, Ng WH, Tian Z, Yap J, Baccarini M, Chen Z, et al. Activating mutations in MEK1 enhance homodimerization and promote tumorigenesis. Sci Signal. 2018;11(554):eaar6795.
Not in our library10.1126/scisignal.aar6795
47.
Wang HG, Rapp UR, Reed JC. Bcl-2 targets the protein kinase Raf-1 to mitochondria. Cell. 1996;87(4):629-638.
Not in our library10.1016/s0092-8674(00)81383-5
48.
Panka DJ, Atkins MB, Mier JW. Targeting the mitogen-activated protein kinase pathway in the treatment of malignant melanoma. Clin Cancer Res. 2006;12(7 Pt 2):2371s-2375s.
Not in our library10.1158/1078-0432.ccr-05-2539
49.
Raf induces NF-κB by membrane shuttle kinase MEKK1, a signaling pathway critical for transformation · 2000
Not checked
50.
Troppmair J, Hartkamp J, Rapp UR. Activation of NF-kappa B by oncogenic Raf in HEK 293 cells occurs through autocrine recruitment of the stress kinase cascade. Oncogene. 1998;17(6):685-690.
Not in our library10.1038/sj.onc.1201981
51.
Norris JL, Baldwin AS. Oncogenic Ras enhances NF-kappaB transcriptional activity through Raf-dependent and Raf-independent mitogen-activated protein kinase signaling pathways. J Biol Chem. 1999;274(20):13841-13846.
Not in our library10.1074/jbc.274.20.13841
52.
Downward J. Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer. 2003;3(1):11-22.
Not in our library10.1038/nrc969
53.
Wojnowski L, Stancato LF, Larner AC, Rapp UR, Zimmer A. Overlapping and specific functions of Braf and Craf-1 proto-oncogenes during mouse embryogenesis. Mech Dev. 2000;91(1-2):97-104.
Not in our library10.1016/s0925-4773(99)00276-2
54.
Zhang Z, Kobayashi S, Borczuk AC, Leidner RS, Laframboise T, Levine AD, et al. Dual specificity phosphatase 6 (DUSP6) is an ETS-regulated negative feedback mediator of oncogenic ERK signaling in lung cancer cells. Carcinogenesis. 2010;31(4):577-586.
Not in our library10.1093/carcin/bgq020
55.
Ekerot M, Stavridis MP, Delavaine L, Mitchell MP, Staples C, Owens DM, et al. Negative-feedback regulation of FGF signalling by DUSP6/MKP-3 is driven by ERK1/2 and mediated by Ets factor binding to a conserved site within the DUSP6/MKP-3 gene promoter. Biochem J. 2008;412(2):287-298.
Not in our library10.1042/bj20071512
56.
Brummer T, Naegele H, Reth M, Misawa Y. Identification of novel ERK-mediated feedback phosphorylation sites at the C-terminus of B-Raf. Oncogene. 2003;22(55):8823-8834.
Not in our library10.1038/sj.onc.1207185
57.
Dougherty MK, Muller J, Ritt DA, Zhou M, Zhou XZ, Copeland TD, et al. Regulation of Raf-1 by direct feedback phosphorylation. Mol Cell. 2005;17(2):215-224.
Not in our library10.1016/j.molcel.2004.11.055
58.
Ritt DA, Monson DM, Specht SI, Morrison DK. Impact of feedback phosphorylation and Raf heterodimerization on normal and mutant B-Raf signaling. Mol Cell Biol. 2010;30(3):806-819.
Not in our library10.1128/mcb.00569-09
59.
Valis K, Novak P. Targeting ERK-Hippo interplay in cancer therapy. Int J Mol Sci. 2020;21(9):3236.
Not in our library10.3390/ijms21093236
60.
Ohm AM, Affandi T, Reyland ME. EGF receptor and PKCdelta kinase activate DNA damage-induced pro-survival and pro-apoptotic signaling via biphasic activation of ERK and MSK1 kinases. J Biol Chem. 2019;294(12):4488-4497.
Not in our library10.1074/jbc.ra118.006944
61.
Unni AM, Harbourne B, Oh MH, Wild S, Ferrarone JR, Lockwood WW, et al. Hyperactivation of ERK by multiple mechanisms is toxic to RTK-RAS mutation-driven lung adenocarcinoma cells. Elife. 2018;7:e33718.
Not in our library10.7554/elife.33718
62.
Cagnol S, Chambard JC. ERK and cell death: mechanisms of ERK-induced cell death—apoptosis, autophagy and senescence. FEBS J. 2010;277(1):2-21.
Not in our library10.1111/j.1742-4658.2009.07366.x
63.
Targeting Aberrant RAS/RAF/MEK/ERK Signaling for Cancer Therapy · 2020
No notice
64.
Jun S, Lee S, Kim HC, Ng C, Schneider AM, Ji H, et al. PAF-mediated MAPK signaling hyperactivation via LAMTOR3 induces pancreatic tumorigenesis. Cell Rep. 2013;5(2):314-322.
Not in our library10.1016/j.celrep.2013.09.026
65.
Drosten M, Sum EY, Lechuga CG, Simon-Carrasco L, Jacob HK, Garcia-Medina R, et al. Loss of p53 induces cell proliferation via Ras-independent activation of the Raf/Mek/Erk signaling pathway. Proc Natl Acad Sci U S A. 2014;111(42):15155-15160.
Not in our library10.1073/pnas.1417549111
66.
Xu S, Khoo S, Dang A, Witt S, Do V, Zhen E, et al. Differential regulation of mitogen-activated protein/ERK kinase (MEK)1 and MEK2 and activation by a Ras-independent mechanism. Mol Endocrinol. 1997;11(11):1618-1625.
Not in our library10.1210/mend.11.11.0010
67.
Maik-Rachline G, Seger R. The ERK cascade inhibitors: towards overcoming resistance. Drug Resist Updat. 2016;25:1-12.
Not in our library10.1016/j.drup.2015.12.001
68.
Aoki Y, Niihori T, Inoue S, Matsubara Y. Recent advances in RASopathies. J Hum Genet. 2016;61(1):33-39.
Not in our library10.1038/jhg.2015.114
69.
Quilliam LA, Castro AF, Rogers-Graham KS, Martin CB, Der CJ, Bi C. M-Ras/R-Ras3, a transforming ras protein regulated by Sos1, GRF1, and p120 Ras GTPase-activating protein, interacts with the putative Ras effector AF6. J Biol Chem. 1999;274(34):23850-23857.
Not in our library10.1074/jbc.274.34.23850
70.
Skoulidis F, Heymach JV. Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy. Nat Rev Cancer. 2019;19(9):495-509.
Not in our library10.1038/s41568-019-0179-8
71.
Martinez P, Mak RH, Oxnard GR. Targeted therapy as an alternative to whole-brain radiotherapy in EGFR-mutant or ALK-positive non-small-cell lung cancer with brain metastases. JAMA Oncol. 2017;3(9):1274-1275.
Not in our library10.1001/jamaoncol.2017.1047
72.
Loibl S, Gianni L. HER2-positive breast cancer. Lancet. 2017;389(10087):2415-2429.
Not in our library10.1016/s0140-6736(16)32417-5
73.
Katoh M. Fibroblast growth factor receptors as treatment targets in clinical oncology. Nat Rev Clin Oncol. 2019;16(2):105-122.
Not in our library10.1038/s41571-018-0115-y
74.
Hobbs GA, Der CJ, Rossman KL. RAS isoforms and mutations in cancer at a glance. J Cell Sci. 2016;129(7):1287-1292.
Not in our library10.1242/jcs.182873
75.
Prior IA, Lewis PD, Mattos C. A comprehensive survey of Ras mutations in cancer. Cancer Res. 2012;72(10):2457-2467.
Not in our library10.1158/0008-5472.can-11-2612
76.
Tessoulin B, Moreau-Aubry A, Descamps G, Gomez-Bougie P, Maiga S, Gaignard A, et al. Whole-exon sequencing of human myeloma cell lines shows mutations related to myeloma patients at relapse with major hits in the DNA regulation and repair pathways. J Hematol Oncol. 2018;11(1):137.
Not in our library10.1186/s13045-018-0679-0
77.
Lavoie H, Therrien M. Regulation of RAF protein kinases in ERK signalling. Nat Rev Mol Cell Biol. 2015;16(5):281-298.
Not in our library10.1038/nrm3979
78.
Tiacci E, Pettirossi V, Schiavoni G, Falini B. Genomics of Hairy Cell Leukemia. J Clin Oncol. 2017;35(9):1002-1010.
Not in our library10.1200/jco.2016.71.1556
79.
Punt CJ, Koopman M, Vermeulen L. From tumour heterogeneity to advances in precision treatment of colorectal cancer. Nat Rev Clin Oncol. 2017;14(4):235-246.
Not in our library10.1038/nrclinonc.2016.171
80.
Bible KC, Ryder M. Evolving molecularly targeted therapies for advanced-stage thyroid cancers. Nat Rev Clin Oncol. 2016;13(7):403-416.
Not in our library10.1038/nrclinonc.2016.19
81.
Schadendorf D, Fisher DE, Garbe C, Gershenwald JE, Grob JJ, Halpern A, et al. Melanoma. Nat Rev Dis Primers. 2015;1:15003.
Not in our library10.1038/nrdp.2015.3
82.
Emery CM, Vijayendran KG, Zipser MC, Sawyer AM, Niu L, Kim JJ, et al. MEK1 mutations confer resistance to MEK and B-RAF inhibition. Proc Natl Acad Sci U S A. 2009;106(48):20411-20416.
Not in our library10.1073/pnas.0905833106
83.
Gao Y, Maria A, Na N, da Cruz Paula A, Gorelick AN, Hechtman JF, et al. V211D mutation in MEK1 causes resistance to MEK inhibitors in colon cancer. Cancer Discov. 2019;9(9):1182-1191.
Not in our library10.1158/2159-8290.cd-19-0356
84.
Kakadia S, Yarlagadda N, Awad R, Kundranda M, Niu J, Naraev B, et al. Mechanisms of resistance to BRAF and MEK inhibitors and clinical update of US Food and Drug Administration-approved targeted therapy in advanced melanoma. Onco Targets Ther. 2018;11:7095-7107.
Not in our library10.2147/ott.s182721
85.
Goetz EM, Ghandi M, Treacy DJ, Wagle N, Garraway LA. ERK mutations confer resistance to mitogen-activated protein kinase pathway inhibitors. Cancer Res. 2014;74(23):7079-7089.
Not in our library10.1158/0008-5472.can-14-2073
86.
Cox AD, Fesik SW, Kimmelman AC, Luo J, Der CJ. Drugging the undruggable RAS: mission possible? Nat Rev Drug Discov. 2014;13(11):828-851.
Not in our library10.1038/nrd4389
87.
Westover KD, Janne PA, Gray NS. Progress on covalent inhibition of KRAS(G12C). Cancer Discov. 2016;6(3):233-234.
Not in our library10.1158/2159-8290.cd-16-0092
88.
Lito P, Solomon M, Li LS, Hansen R, Rosen N. Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism. Science. 2016;351(6273):604-608.
Not in our library10.1126/science.aad6204
89.
Janes MR, Zhang J, Li LS, Hansen R, Peters U, Guo X, et al. Targeting KRAS Mutant cancers with a covalent G12C-specific inhibitor. Cell. 2018;172(3):578-589.
Not in our library10.1016/j.cell.2018.01.006
90.
Hallin J, Engstrom LD, Hargis L, Calinisan A, Aranda R, Briere DM, 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(1):54-71.
Not in our library10.1158/2159-8290.cd-19-1167
91.
Canon J, Rex K, Saiki AY, Mohr C, Cooke K, Bagal D, et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature. 2019;575(7781):217-223.
Not in our library10.1038/s41586-019-1694-1
92.
Nichols RJ, Haderk F, Stahlhut C, Schulze CJ, Hemmati G, Wildes D, et al. RAS nucleotide cycling underlies the SHP2 phosphatase dependence of mutant BRAF-, NF1- and RAS-driven cancers. Nat Cell Biol. 2018;20(9):1064-1073.
Not in our library10.1038/s41556-018-0169-1
93.
Ryan MB, Fece de la Cruz F, Phat S, Myers DT, Wong E, Shahzade HA, et al. Vertical pathway inhibition overcomes adaptive feedback resistance to KRAS(G12C) inhibition. Clin Cancer Res. 2020;26(7):1633-1643.
Not in our library10.1158/1078-0432.ccr-19-3523
94.
Bond MJ, Chu L, Nalawansha DA, Li K, Crews CM. Targeted degradation of oncogenic KRASG12C by VHL-recruiting PROTACs. ACS Central Sci. 2020. 10.1021/acscentsci.0c00411.
Not in our library10.1021/acscentsci.0c00411
95.
Zeng M, Xiong Y, Safaee N, Nowak RP, Donovan KA, Yuan CJ, et al. Exploring targeted degradation strategy for oncogenic KRAS(G12C). Cell Chem Biol. 2020;27(1):19-31 e6.
Not in our library10.1016/j.chembiol.2019.12.006
96.
Stalnecker CA, Der CJ. RAS, wanted dead or alive: advances in targeting RAS mutant cancers. Sci Signal. 2020;13(624):eaay6013.
Not in our library10.1126/scisignal.aay6013
97.
Athuluri-Divakar SK, Vasquez-Del Carpio R, Dutta K, Baker SJ, Cosenza SC, Basu I, et al. A small molecule RAS-mimetic disrupts RAS association with effector proteins to block signaling. Cell. 2016;165(3):643-655.
Not in our library10.1016/j.cell.2016.03.045
98.
Hymowitz SG, Malek S. Targeting the MAPK pathway in RAS mutant cancers. Cold Spring Harb Perspect Med. 2018;8(11):a031492.
Not in our library10.1101/cshperspect.a031492
99.
Flaherty K, Puzanov I, Sosman J, Kim K, Ribas A, McArthur G, et al. Phase I study of PLX4032: proof of concept for V600E BRAF mutation as a therapeutic target in human cancer. J Clin Oncol. 2009;27(15_suppl):9000.
Not in our library
100.
Tsai J, Lee JT, Wang W, Zhang J, Cho H, Mamo S, et al. Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proc Natl Acad Sci U S A. 2008;105(8):3041-3046.
Not in our library10.1073/pnas.0711741105
101.
Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380(9839):358-365.
Not in our library10.1016/s0140-6736(12)60868-x
102.
Yao Z, Gao Y, Su W, Yaeger R, Tao J, Na N, et al. RAF inhibitor PLX8394 selectively disrupts BRAF dimers and RAS-independent BRAF-mutant-driven signaling. Nat Med. 2019;25(2):284-291.
Not in our library10.1038/s41591-018-0274-5
103.
Herrero A, Pinto A, Colon-Bolea P, Casar B, Jones M, Agudo-Ibanez L, et al. Small molecule inhibition of ERK dimerization prevents tumorigenesis by RAS-ERK pathway oncogenes. Cancer Cell. 2015;28(2):170-182.
Not in our library10.1016/j.ccell.2015.07.001
104.
Gunderwala AY, Nimbvikar AA, Cope NJ, Li Z, Wang Z. Development of allosteric BRAF peptide inhibitors targeting the dimer interface of BRAF. ACS Chem Biol. 2019;14(7):1471-1480.
Not in our library10.1021/acschembio.9b00191
105.
From basic research to clinical development of MEK1/2 inhibitors for cancer therapy · 2010
No notice
106.
Huang T, Karsy M, Zhuge J, Zhong M, Liu D. B-Raf and the inhibitors: from bench to bedside. J Hematol Oncol. 2013;6:30.
Not in our library10.1186/1756-8722-6-30
107.
MEK and the inhibitors: from bench to bedside · 2013
No notice
108.
Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363(9):809-819.
Not in our library10.1056/nejmoa1002011
109.
Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26):2507-2516.
Not in our library10.1056/nejmoa1103782
110.
Sosman JA, Kim KB, Schuchter L, Gonzalez R, Pavlick AC, Weber JS, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012;366(8):707-714.
Not in our library10.1056/nejmoa1112302
111.
Larkin J, Ascierto PA, Dreno B, Atkinson V, Liszkay G, Maio M, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371(20):1867-1876.
Not in our library10.1056/nejmoa1408868
112.
Long GV, Weber JS, Infante JR, Kim KB, Daud A, Gonzalez R, et al. Overall survival and durable responses in patients with BRAF V600-mutant metastatic melanoma receiving dabrafenib combined with trametinib. J Clin Oncol. 2016;34(8):871-878.
Not in our library10.1200/jco.2015.62.9345
113.
Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372(1):30-39.
Not in our library10.1056/nejmoa1412690
114.
Planchard D, Smit EF, Groen HJM, Mazieres J, Besse B, Helland A, et al. Dabrafenib plus trametinib in patients with previously untreated BRAF(V600E)-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial. Lancet Oncol. 2017;18(10):1307-1316.
Not in our library10.1016/s1470-2045(17)30679-4
115.
Subbiah V, Kreitman RJ, Wainberg ZA, Cho JY, Schellens JHM, Soria JC, et al. Dabrafenib and trametinib treatment in patients with locally advanced or metastatic BRAF V600-mutant anaplastic thyroid cancer. J Clin Oncol. 2018;36(1):7-13.
Not in our library10.1200/jco.2017.73.6785
116.
Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367(18):1694-1703.
Not in our library10.1056/nejmoa1210093
117.
Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. 2014;371(20):1877-1888.
Not in our library10.1056/nejmoa1406037
118.
Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H, et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature. 2010;468(7326):973-977.
Not in our library10.1038/nature09626
119.
Wilson TR, Fridlyand J, Yan Y, Penuel E, Burton L, Chan E, et al. Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature. 2012;487(7408):505-509.
Not in our library10.1038/nature11249
120.
Poulikakos PI, Zhang C, Bollag G, Shokat KM, Rosen N. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature. 2010;464(7287):427-430.
Not in our library10.1038/nature08902
121.
Zhang C, Spevak W, Zhang Y, Burton EA, Ma Y, Habets G, et al. RAF inhibitors that evade paradoxical MAPK pathway activation. Nature. 2015;526(7574):583-586.
Not in our library10.1038/nature14982
122.
RAF dimer inhibition enhances the antitumor activity of MEK inhibitors in K‐RAS mutant tumors · 2020
Not checked
123.
Desai J, Gan H, Barrow C, Jameson MB, Solomon B, Atkinson V, et al. Abstract CT002: a phase IB study of RAF dimer inhibitor BGB-283 in patients with B-RAF or K-RAS/N-RAS mutated solid tumors. Cancer Res. 2017;77(13 Supplement):CT002-CT0CT.
Not in our library
124.
Sun Y, Alberta JA, Pilarz C, Calligaris D, Chadwick EJ, Ramkissoon SH, et al. A brain-penetrant RAF dimer antagonist for the noncanonical BRAF oncoprotein of pediatric low-grade astrocytomas. Neuro Oncol. 2017;19(6):774-785.
Not in our library10.1093/neuonc/now261
125.
Tang Z, Yuan X, Du R, Cheung SH, Zhang G, Wei J, et al. BGB-283, a novel RAF kinase and EGFR inhibitor, displays potent antitumor activity in BRAF-mutated colorectal cancers. Mol Cancer Ther. 2015;14(10):2187-2197.
Not in our library10.1158/1535-7163.mct-15-0262
126.
Saturno G, Lopes F, Girotti MR, Niculescu-Duvaz I, Niculescu-Duvaz D, Zambon A, et al. Abstract LB-212: therapeutic efficacy of the paradox-breaking panRAF and SRC drug CCT3833/BAL3833 in KRAS-driven cancer models. Cancer Res. 2016;76(14 Supplement):LB-212-LB-2LB.
Not in our library
127.
Martinez-Garcia M, Banerji U, Albanell J, Bahleda R, Dolly S, Kraeber-Bodere F, et al. First-in-human, phase I dose-escalation study of the safety, pharmacokinetics, and pharmacodynamics of RO5126766, a first-in-class dual MEK/RAF inhibitor in patients with solid tumors. Clin Cancer Res. 2012;18(17):4806-4819.
Not in our library10.1158/1078-0432.ccr-12-0742
128.
Ishii N, Harada N, Joseph EW, Ohara K, Miura T, Sakamoto 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(13):4050-4060.
Not in our library10.1158/0008-5472.can-12-3937
129.
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(11):e113217.
Not in our library10.1371/journal.pone.0113217
130.
Knauf JA, Luckett KA, Chen KY, Voza F, Socci ND, Ghossein R, et al. Hgf/Met activation mediates resistance to BRAF inhibition in murine anaplastic thyroid cancers. J Clin Invest. 2018;128(9):4086-4097.
Not in our library10.1172/jci120966
131.
Sullivan RJ, Infante JR, Janku F, Wong DJL, Sosman JA, Keedy V, et al. First-in-class ERK1/2 inhibitor ulixertinib (BVD-523) in patients with MAPK mutant advanced solid tumors: results of a phase I dose-escalation and expansion study. Cancer Discov. 2018;8(2):184-195.
Not in our library10.1158/2159-8290.cd-17-1119
132.
Moschos SJ, Sullivan RJ, Hwu WJ, Ramanathan RK, Adjei AA, Fong PC, et al. Development of MK-8353, an orally administered ERK1/2 inhibitor, in patients with advanced solid tumors. JCI Insight. 2018;3(4):e92352.
Not in our library10.1172/jci.insight.92352
133.
Coussy F, El Botty R, Lavigne M, Gu C, Fuhrmann L, Briaux A, et al. Combination of PI3K and MEK inhibitors yields durable remission in PDX models of PIK3CA-mutated metaplastic breast cancers. J Hematol Oncol. 2020;13(1):13.
Not in our library10.1186/s13045-020-0846-y
134.
Carlson CA, Kim KH. Regulation of hepatic acetyl coenzyme A carboxylase by phosphorylation and dephosphorylation. J Biol Chem. 1973;248(1):378-380.
Not in our library
135.
Yeh LA, Lee KH, Kim KH. Regulation of rat liver acetyl-CoA carboxylase. Regulation of phosphorylation and inactivation of acetyl-CoA carboxylase by the adenylate energy charge. J Biol Chem. 1980;255(6):2308-2314.
Not in our library
136.
Ly S, Kim KH. Inactivation of hepatic acetyl-CoA carboxylase by catecholamine and its agonists through the alpha-adrenergic receptors. J Biol Chem. 1981;256(22):11585-11590.
Not in our library
137.
Lent B, Kim KH. Purification and properties of a kinase which phosphorylates and inactivates acetyl-CoA carboxylase. J Biol Chem. 1982;257(4):1897-1901.
Not in our library
138.
Carling D, Zammit VA, Hardie DG. A common bicyclic protein kinase cascade inactivates the regulatory enzymes of fatty acid and cholesterol biosynthesis. FEBS Lett. 1987;223(2):217-222.
Not in our library10.1016/0014-5793(87)80292-2
139.
Hardie DG. AMPK—sensing energy while talking to other signaling pathways. Cell Metab. 2014;20(6):939-952.
Not in our library10.1016/j.cmet.2014.09.013
140.
Oakhill JS, Scott JW, Kemp BE. AMPK functions as an adenylate charge-regulated protein kinase. Trends Endocrinol Metab. 2012;23(3):125-132.
Not in our library10.1016/j.tem.2011.12.006
141.
Carling D, Thornton C, Woods A, Sanders MJ. AMP-activated protein kinase: new regulation, new roles? Biochem J. 2012;445(1):11-27.
Not in our library10.1042/bj20120546
142.
Hardie DG, Schaffer BE, Brunet A. AMPK: an energy-sensing pathway with multiple inputs and outputs. Trends Cell Biol. 2016;26(3):190-201.
Not in our library10.1016/j.tcb.2015.10.013
143.
Davies SP, Hawley SA, Woods A, Carling D, Haystead TA, Hardie DG. Purification of the AMP-activated protein kinase on ATP-gamma-sepharose and analysis of its subunit structure. Eur J Biochem. 1994;223(2):351-357.
Not in our library10.1111/j.1432-1033.1994.tb19001.x
144.
Mitchelhill KI, Stapleton D, Gao G, House C, Michell B, Katsis F, et al. Mammalian AMP-activated protein kinase shares structural and functional homology with the catalytic domain of yeast Snf1 protein kinase. J Biol Chem. 1994;269(4):2361-2364.
Not in our library
145.
Dasgupta B, Chhipa RR. Evolving lessons on the complex role of AMPK in normal physiology and cancer. Trends Pharmacol Sci. 2016;37(3):192-206.
Not in our library10.1016/j.tips.2015.11.007
146.
The strange case of AMPK and cancer: Dr Jekyll or Mr Hyde? · 2019
No notice
147.
AMP ‐activated protein kinase: a cellular energy sensor that comes in 12 flavours · 2016
No notice
148.
Steinberg GR, Carling D. AMP-activated protein kinase: the current landscape for drug development. Nat Rev Drug Discov. 2019;18(7):527-551.
Not in our library10.1038/s41573-019-0019-2
149.
Quentin T, Kitz J, Steinmetz M, Poppe A, Bar K, Kratzner R. Different expression of the catalytic alpha subunits of the AMP activated protein kinase—an immunohistochemical study in human tissue. Histol Histopathol. 2011;26(5):589-596.
Not in our library10.14670/hh-26.589
150.
Dasgupta B, Ju JS, Sasaki Y, Liu X, Jung SR, Higashida K, et al. The AMPK beta2 subunit is required for energy homeostasis during metabolic stress. Mol Cell Biol. 2012;32(14):2837-2848.
Not in our library10.1128/mcb.05853-11
151.
Chen Z, Heierhorst J, Mann RJ, Mitchelhill KI, Michell BJ, Witters LA, et al. Expression of the AMP-activated protein kinase beta1 and beta2 subunits in skeletal muscle. FEBS Lett. 1999;460(2):343-348.
Not in our library10.1016/s0014-5793(99)01371-x
152.
Wu J, Puppala D, Feng X, Monetti M, Lapworth AL, Geoghegan KF. Chemoproteomic analysis of intertissue and interspecies isoform diversity of AMP-activated protein kinase (AMPK). J Biol Chem. 2013;288(50):35904-35912.
Not in our library10.1074/jbc.m113.508747
153.
Jorgensen SB, Wojtaszewski JF, Viollet B, Andreelli F, Birk JB, Hellsten Y, et al. Effects of alpha-AMPK knockout on exercise-induced gene activation in mouse skeletal muscle. FASEB J. 2005;19(9):1146-1148.
Not in our library10.1096/fj.04-3144fje
154.
Shaw RJ, Kosmatka M, Bardeesy N, Hurley RL, Witters LA, DePinho RA, et al. The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc Natl Acad Sci U S A. 2004;101(10):3329-3335.
Not in our library10.1073/pnas.0308061100
155.
Woods A, Johnstone SR, Dickerson K, Leiper FC, Fryer LG, Neumann D, et al. LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr Biol. 2003;13(22):2004-2008.
Not in our library10.1016/j.cub.2003.10.031
156.
Hawley SA, Pan DA, Mustard KJ, Ross L, Bain J, Edelman AM, et al. Calmodulin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab. 2005;2(1):9-19.
Not in our library10.1016/j.cmet.2005.05.009
157.
Hurley RL, Anderson KA, Franzone JM, Kemp BE, Means AR, Witters LA. The Ca2+/calmodulin-dependent protein kinase kinases are AMP-activated protein kinase kinases. J Biol Chem. 2005;280(32):29060-29066.
Not in our library10.1074/jbc.m503824200
158.
Woods A, Dickerson K, Heath R, Hong SP, Momcilovic M, Johnstone SR, et al. Ca2+/calmodulin-dependent protein kinase kinase-beta acts upstream of AMP-activated protein kinase in mammalian cells. Cell Metab. 2005;2(1):21-33.
Not in our library10.1016/j.cmet.2005.06.005
159.
Anderson KA, Ribar TJ, Lin F, Noeldner PK, Green MF, Muehlbauer MJ, et al. Hypothalamic CaMKK2 contributes to the regulation of energy balance. Cell Metab. 2008;7(5):377-388.
Not in our library10.1016/j.cmet.2008.02.011
160.
Stahmann N, Woods A, Carling D, Heller R. Thrombin activates AMP-activated protein kinase in endothelial cells via a pathway involving Ca2+/calmodulin-dependent protein kinase kinase beta. Mol Cell Biol. 2006;26(16):5933-5945.
Not in our library10.1128/mcb.00383-06
161.
Thornton C, Sardini A, Carling D. Muscarinic receptor activation of AMP-activated protein kinase inhibits orexigenic neuropeptide mRNA expression. J Biol Chem. 2008;283(25):17116-17122.
Not in our library10.1074/jbc.m708987200
162.
Andersson U, Filipsson K, Abbott CR, Woods A, Smith K, Bloom SR, et al. AMP-activated protein kinase plays a role in the control of food intake. J Biol Chem. 2004;279(13):12005-12008.
Not in our library10.1074/jbc.c300557200
163.
Zhang CS, Hawley SA, Zong Y, Li M, Wang Z, Gray A, et al. Fructose-1,6-bisphosphate and aldolase mediate glucose sensing by AMPK. Nature. 2017;548(7665):112-116.
Not in our library10.1038/nature23275
164.
Ingebritsen TS, Geelen MJ, Parker RA, Evenson KJ, Gibson DM. Modulation of hydroxymethylglutaryl-CoA reductase activity, reductase kinase activity, and cholesterol synthesis in rat hepatocytes in response to insulin and glucagon. J Biol Chem. 1979;254(20):9986-9989.
Not in our library
165.
Loh K, Tam S, Murray-Segal L, Huynh K, Meikle PJ, Scott JW, et al. Inhibition of adenosine monophosphate-activated protein kinase-3-hydroxy-3-methylglutaryl coenzyme A reductase signaling leads to hypercholesterolemia and promotes hepatic steatosis and insulin resistance. Hepatol Commun. 2019;3(1):84-98.
Not in our library10.1002/hep4.1279
166.
Menendez JA, Lupu R. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer. 2007;7(10):763-777.
Not in our library10.1038/nrc2222
167.
Hoffman NJ, Parker BL, Chaudhuri R, Fisher-Wellman KH, Kleinert M, Humphrey SJ, et al. Global phosphoproteomic analysis of human skeletal muscle reveals a network of exercise-regulated kinases and AMPK substrates. Cell Metab. 2015;22(5):922-935.
Not in our library10.1016/j.cmet.2015.09.001
168.
Wan Z, Root-McCaig J, Castellani L, Kemp BE, Steinberg GR, Wright DC. Evidence for the role of AMPK in regulating PGC-1 alpha expression and mitochondrial proteins in mouse epididymal adipose tissue. Obesity (Silver Spring). 2014;22(3):730-738.
Not in our library10.1002/oby.20605
169.
Zhang H, Guan M, Townsend KL, Huang TL, An D, Yan X, et al. MicroRNA-455 regulates brown adipogenesis via a novel HIF1an-AMPK-PGC1alpha signaling network. EMBO Rep. 2015;16(10):1378-1393.
Not in our library10.15252/embr.201540837
170.
Ducommun S, Deak M, Sumpton D, Ford RJ, Nunez Galindo A, Kussmann M, et al. Motif affinity and mass spectrometry proteomic approach for the discovery of cellular AMPK targets: identification of mitochondrial fission factor as a new AMPK substrate. Cell Signal. 2015;27(5):978-988.
Not in our library10.1016/j.cellsig.2015.02.008
171.
Toyama EQ, Herzig S, Courchet J, Lewis TL, Loson OC, Hellberg K, et al. Metabolism. AMP-activated protein kinase mediates mitochondrial fission in response to energy stress. Science. 2016;351(6270):275-281.
Not in our library10.1126/science.aab4138
172.
The Association of AMPK with ULK1 Regulates Autophagy · 2010
No notice
173.
Behrends C, Sowa ME, Gygi SP, Harper JW. Network organization of the human autophagy system. Nature. 2010;466(7302):68-76.
Not in our library10.1038/nature09204
174.
Weerasekara VK, Panek DJ, Broadbent DG, Mortenson JB, Mathis AD, Logan GN, et al. Metabolic-stress-induced rearrangement of the 14-3-3zeta interactome promotes autophagy via a ULK1- and AMPK-regulated 14-3-3zeta interaction with phosphorylated Atg9. Mol Cell Biol. 2014;34(24):4379-4388.
Not in our library10.1128/mcb.00740-14
175.
Zhang D, Wang W, Sun X, Xu D, Wang C, Zhang Q, et al. AMPK regulates autophagy by phosphorylating BECN1 at threonine 388. Autophagy. 2016;12(9):1447-1459.
Not in our library10.1080/15548627.2016.1185576
176.
Taylor EB, An D, Kramer HF, Yu H, Fujii NL, Roeckl KS, et al. Discovery of TBC1D1 as an insulin-, AICAR-, and contraction-stimulated signaling nexus in mouse skeletal muscle. J Biol Chem. 2008;283(15):9787-9796.
Not in our library10.1074/jbc.m708839200
177.
Treebak JT, Glund S, Deshmukh A, Klein DK, Long YC, Jensen TE, et al. AMPK-mediated AS160 phosphorylation in skeletal muscle is dependent on AMPK catalytic and regulatory subunits. Diabetes. 2006;55(7):2051-2058.
Not in our library10.2337/db06-0175
178.
Liu Y, Lai YC, Hill EV, Tyteca D, Carpentier S, Ingvaldsen A, et al. Phosphatidylinositol 3-phosphate 5-kinase (PIKfyve) is an AMPK target participating in contraction-stimulated glucose uptake in skeletal muscle. Biochem J. 2013;455(2):195-206.
Not in our library10.1042/bj20130644
179.
Phospholipase D1 mediates AMP-activated protein kinase signaling for glucose uptake. · 2010
Not checked
180.
Abbud W, Habinowski S, Zhang JZ, Kendrew J, Elkairi FS, Kemp BE, et al. Stimulation of AMP-activated protein kinase (AMPK) is associated with enhancement of Glut1-mediated glucose transport. Arch Biochem Biophys. 2000;380(2):347-352.
Not in our library10.1006/abbi.2000.1935
181.
Fryer LG, Foufelle F, Barnes K, Baldwin SA, Woods A, Carling D. Characterization of the role of the AMP-activated protein kinase in the stimulation of glucose transport in skeletal muscle cells. Biochem J. 2002;363(Pt 1):167-174.
Not in our library10.1042/0264-6021:3630167
182.
Marsin AS, Bertrand L, Rider MH, Deprez J, Beauloye C, Vincent MF, et al. Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia. Curr Biol. 2000;10(20):1247-1255.
Not in our library10.1016/s0960-9822(00)00742-9
183.
Bultot L, Guigas B, Von Wilamowitz-Moellendorff A, Maisin L, Vertommen D, Hussain N, et al. AMP-activated protein kinase phosphorylates and inactivates liver glycogen synthase. Biochem J. 2012;443(1):193-203.
Not in our library10.1042/bj20112026
184.
Amino acid homeostasis and signalling in mammalian cells and organisms · 2017
No notice
185.
Efeyan A, Zoncu R, Sabatini DM. Amino acids and mTORC1: from lysosomes to disease. Trends Mol Med. 2012;18(9):524-533.
Not in our library10.1016/j.molmed.2012.05.007
186.
Hu CA, Wu Z, Wang J. Amino acids and autophagy: their crosstalk, interplay and interlock. Amino Acids. 2015;47(10):2035-2036.
Not in our library10.1007/s00726-015-2098-7
187.
Chan AY, Soltys CL, Young ME, Proud CG, Dyck JR. Activation of AMP-activated protein kinase inhibits protein synthesis associated with hypertrophy in the cardiac myocyte. J Biol Chem. 2004;279(31):32771-32779.
Not in our library10.1074/jbc.m403528200
188.
Saha AK, Xu XJ, Lawson E, Deoliveira R, Brandon AE, Kraegen EW, et al. Downregulation of AMPK accompanies leucine- and glucose-induced increases in protein synthesis and insulin resistance in rat skeletal muscle. Diabetes. 2010;59(10):2426-2434.
Not in our library10.2337/db09-1870
189.
Gleason CE, Lu D, Witters LA, Newgard CB, Birnbaum MJ. The role of AMPK and mTOR in nutrient sensing in pancreatic beta-cells. J Biol Chem. 2007;282(14):10341-10351.
Not in our library10.1074/jbc.m610631200
190.
A systems study reveals concurrent activation of AMPK and mTOR by amino acids · 2016
No notice
191.
Shaw RJ, Bardeesy N, Manning BD, Lopez L, Kosmatka M, DePinho RA, et al. The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell. 2004;6(1):91-99.
Not in our library10.1016/j.ccr.2004.06.007
192.
Faubert B, Boily G, Izreig S, Griss T, Samborska B, Dong Z, et al. AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. Cell Metab. 2013;17(1):113-124.
Not in our library10.1016/j.cmet.2012.12.001
193.
Chou CC, Lee KH, Lai IL, Wang D, Mo X, Kulp SK, et al. AMPK reverses the mesenchymal phenotype of cancer cells by targeting the Akt-MDM2-Foxo3a signaling axis. Cancer Res. 2014;74(17):4783-4795.
Not in our library10.1158/0008-5472.can-14-0135
194.
Energy Stress Regulates Hippo-YAP Signaling Involving AMPK-Mediated Regulation of Angiomotin-like 1 Protein · 2014
Not checked
195.
Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell. 2008;30(2):214-226.
Not in our library10.1016/j.molcel.2008.03.003
196.
Choo AY, Kim SG, Vander Heiden MG, Mahoney SJ, Vu H, Yoon SO, et al. Glucose addiction of TSC null cells is caused by failed mTORC1-dependent balancing of metabolic demand with supply. Mol Cell. 2010;38(4):487-499.
Not in our library10.1016/j.molcel.2010.05.007
197.
Pineda CT, Ramanathan S, Fon Tacer K, Weon JL, Potts MB, Ou YH, et al. Degradation of AMPK by a cancer-specific ubiquitin ligase. Cell. 2015;160(4):715-728.
Not in our library10.1016/j.cell.2015.01.034
198.
Wan L, Xu K, Wei Y, Zhang J, Han T, Fry C, et al. Phosphorylation of EZH2 by AMPK suppresses PRC2 methyltransferase activity and oncogenic function. Mol Cell. 2018;69(2):279-91 e5.
Not in our library10.1016/j.molcel.2017.12.024
199.
Wu D, Hu D, Chen H, Shi G, Fetahu IS, Wu F, et al. Glucose-regulated phosphorylation of TET2 by AMPK reveals a pathway linking diabetes to cancer. Nature. 2018;559(7715):637-641.
Not in our library10.1038/s41586-018-0350-5
200.
Kishton RJ, Barnes CE, Nichols AG, Cohen S, Gerriets VA, Siska PJ, et al. AMPK is essential to balance glycolysis and mitochondrial metabolism to control T-ALL cell stress and survival. Cell Metab. 2016;23(4):649-662.
Not in our library10.1016/j.cmet.2016.03.008
201.
Saito Y, Chapple RH, Lin A, Kitano A, Nakada D. AMPK Protects leukemia-initiating cells in myeloid leukemias from metabolic stress in the bone marrow. Cell Stem Cell. 2015;17(5):585-596.
Not in our library10.1016/j.stem.2015.08.019
202.
Jeon SM, Chandel NS, Hay N. AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature. 2012;485(7400):661-665.
Not in our library10.1038/nature11066
203.
Shackelford DB, Abt E, Gerken L, Vasquez DS, Seki A, Leblanc M, et al. LKB1 inactivation dictates therapeutic response of non-small cell lung cancer to the metabolism drug phenformin. Cancer Cell. 2013;23(2):143-158.
Not in our library10.1016/j.ccr.2012.12.008
204.
Liu L, Ulbrich J, Muller J, Wustefeld T, Aeberhard L, Kress TR, et al. Deregulated MYC expression induces dependence upon AMPK-related kinase 5. Nature. 2012;483(7391):608-612.
Not in our library10.1038/nature10927
205.
Kfoury A, Armaro M, Collodet C, Sordet-Dessimoz J, Giner MP, Christen S, et al. AMPK promotes survival of c-Myc-positive melanoma cells by suppressing oxidative stress. EMBO J. 2018;37(5):e97673.
Not in our library10.15252/embj.201797673
206.
The critical role of AMPK in driving Akt activation under stress, tumorigenesis and drug resistance · 2018
No notice
207.
Trillo-Tinoco J, Sierra RA, Mohamed E, Cao Y, de Mingo-Pulido A, Gilvary DL, et al. AMPK alpha-1 intrinsically regulates the function and differentiation of tumor myeloid-derived suppressor cells. Cancer Res. 2019;79(19):5034-5047.
Not in our library10.1158/0008-5472.can-19-0880
208.
Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6(269):pl1.
Not in our library10.1126/scisignal.2004088
209.
Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2(5):401-404.
Not in our library10.1158/2159-8290.cd-12-0095
210.
Collisson EA, Campbell JD, Brooks AN, Berger AH, Lee W, Chmielecki J, et al. Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014;511(7511):543-550.
Not in our library10.1038/nature13385
211.
Chhipa RR, Fan Q, Anderson J, Muraleedharan R, Huang Y, Ciraolo G, et al. AMP kinase promotes glioblastoma bioenergetics and tumour growth. Nat Cell Biol. 2018;20(7):823-835.
Not in our library10.1038/s41556-018-0126-z
212.
Wu N, Zheng B, Shaywitz A, Dagon Y, Tower C, Bellinger G, et al. AMPK-dependent degradation of TXNIP upon energy stress leads to enhanced glucose uptake via GLUT1. Mol Cell. 2013;49(6):1167-1175.
Not in our library10.1016/j.molcel.2013.01.035
213.
Creancier L, Morello D, Mercier P, Prats AC. Fibroblast growth factor 2 internal ribosome entry site (IRES) activity ex vivo and in transgenic mice reveals a stringent tissue-specific regulation. J Cell Biol. 2000;150(1):275-281.
Not in our library10.1083/jcb.150.1.275
214.
Dobson T, Chen J, Krushel LA. Dysregulating IRES-dependent translation contributes to overexpression of oncogenic Aurora A Kinase. Mol Cancer Res. 2013;11(8):887-900.
Not in our library10.1158/1541-7786.mcr-12-0707
215.
Pantovic A, Krstic A, Janjetovic K, Kocic J, Harhaji-Trajkovic L, Bugarski D, et al. Coordinated time-dependent modulation of AMPK/Akt/mTOR signaling and autophagy controls osteogenic differentiation of human mesenchymal stem cells. Bone. 2013;52(1):524-531.
Not in our library10.1016/j.bone.2012.10.024
216.
Yang W, Zheng Y, Xia Y, Ji H, Chen X, Guo F, et al. ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect. Nat Cell Biol. 2012;14(12):1295-1304.
Not in our library10.1038/ncb2629
217.
The ERK and JNK pathways in the regulation of metabolic reprogramming · 2018
No notice
218.
Sang N, Stiehl DP, Bohensky J, Leshchinsky I, Srinivas V, Caro J. MAPK signaling up-regulates the activity of hypoxia-inducible factors by its effects on p300. J Biol Chem. 2003;278(16):14013-14019.
Not in our library10.1074/jbc.m209702200
219.
Sears R, Leone G, DeGregori J, Nevins JR. Ras enhances Myc protein stability. Mol Cell. 1999;3(2):169-179.
Not in our library10.1016/s1097-2765(00)80308-1
220.
Sears R, Nuckolls F, Haura E, Taya Y, Tamai K, Nevins JR. Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability. Genes Dev. 2000;14(19):2501-2514.
Not in our library10.1101/gad.836800
221.
Yeh E, Cunningham M, Arnold H, Chasse D, Monteith T, Ivaldi G, et al. A signalling pathway controlling c-Myc degradation that impacts oncogenic transformation of human cells. Nat Cell Biol. 2004;6(4):308-318.
Not in our library10.1038/ncb1110
222.
Pelletier A, Joly E, Prentki M, Coderre L. Adenosine 5′-monophosphate-activated protein kinase and p38 mitogen-activated protein kinase participate in the stimulation of glucose uptake by dinitrophenol in adult cardiomyocytes. Endocrinology. 2005;146(5):2285-2294.
Not in our library10.1210/en.2004-1565
223.
Zheng B, Jeong JH, Asara JM, Yuan YY, Granter SR, Chin L, et al. Oncogenic B-RAF negatively regulates the tumor suppressor LKB1 to promote melanoma cell proliferation. Mol Cell. 2009;33(2):237-247.
Not in our library10.1016/j.molcel.2008.12.026
224.
Lopez-Cotarelo P, Escribano-Diaz C, Gonzalez-Bethencourt IL, Gomez-Moreira C, Deguiz ML, Torres-Bacete J, et al. A novel MEK-ERK-AMPK signaling axis controls chemokine receptor CCR7-dependent survival in human mature dendritic cells. J Biol Chem. 2015;290(2):827-840.
Not in our library10.1074/jbc.m114.596551
225.
Costanzo-Garvey DL, Pfluger PT, Dougherty MK, Stock JL, Boehm M, Chaika O, et al. KSR2 is an essential regulator of AMP kinase, energy expenditure, and insulin sensitivity. Cell Metab. 2009;10(5):366-378.
Not in our library10.1016/j.cmet.2009.09.010
226.
Fernandez MR, Henry MD, Lewis RE. Kinase suppressor of Ras 2 (KSR2) regulates tumor cell transformation via AMPK. Mol Cell Biol. 2012;32(18):3718-3731.
Not in our library10.1128/mcb.06754-11
227.
Kodiha M, Rassi JG, Brown CM, Stochaj U. Localization of AMP kinase is regulated by stress, cell density, and signaling through the MEK-->ERK1/2 pathway. Am J Physiol Cell Physiol. 2007;293(5):C1427-C1436.
Not in our library10.1152/ajpcell.00176.2007
228.
Freed E, Symons M, Macdonald SG, McCormick F, Ruggieri R. Binding of 14-3-3 proteins to the protein kinase Raf and effects on its activation. Science. 1994;265(5179):1713-1716.
Not in our library10.1126/science.8085158
229.
Fu H, Xia K, Pallas DC, Cui C, Conroy K, Narsimhan RP, et al. Interaction of the protein kinase Raf-1 with 14-3-3 proteins. Science. 1994;266(5182):126-129.
Not in our library10.1126/science.7939632
230.
Verlande A, Krafcikova M, Potesil D, Trantirek L, Zdrahal Z, Elkalaf M, et al. Metabolic stress regulates ERK activity by controlling KSR-RAF heterodimerization. EMBO Rep. 2018;19(2):320-336.
Not in our library10.15252/embr.201744524
231.
Yuan J, Ng WH, Yap J, Chia B, Huang X, Wang M, et al. The AMPK inhibitor overcomes the paradoxical effect of RAF inhibitors through blocking phospho-Ser-621 in the C terminus of CRAF. J Biol Chem. 2018;293(37):14276-14284.
Not in our library10.1074/jbc.ra118.004597
232.
Mischak H, Seitz T, Janosch P, Eulitz M, Steen H, Schellerer M, et al. Negative regulation of Raf-1 by phosphorylation of serine 621. Mol Cell Biol. 1996;16(10):5409-5418.
Not in our library10.1128/mcb.16.10.5409
233.
Shen CH, Yuan P, Perez-Lorenzo R, Zhang Y, Lee SX, Ou Y, et al. Phosphorylation of BRAF by AMPK impairs BRAF-KSR1 association and cell proliferation. Mol Cell. 2013;52(2):161-172.
Not in our library10.1016/j.molcel.2013.08.044
234.
Sprenkle AB, Davies SP, Carling D, Hardie DG, Sturgill TW. Identification of Raf-1 Ser621 kinase activity from NIH 3T3 cells as AMP-activated protein kinase. FEBS Lett. 1997;403(3):254-258.
Not in our library10.1016/s0014-5793(97)00062-8
235.
Petti C, Vegetti C, Molla A, Bersani I, Cleris L, Mustard KJ, et al. AMPK activators inhibit the proliferation of human melanomas bearing the activated MAPK pathway. Melanoma Res. 2012;22(5):341-350.
Not in our library10.1097/cmr.0b013e3283544929
236.
Yuan P, Ito K, Perez-Lorenzo R, Del Guzzo C, Lee JH, Shen CH, et al. Phenformin enhances the therapeutic benefit of BRAF(V600E) inhibition in melanoma. Proc Natl Acad Sci U S A. 2013;110(45):18226-18231.
Not in our library10.1073/pnas.1317577110
237.
Guo JY, Chen HY, Mathew R, Fan J, Strohecker AM, Karsli-Uzunbas G, et al. Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis. Genes Dev. 2011;25(5):460-470.
Not in our library10.1101/gad.2016311
238.
Strohecker AM, Guo JY, Karsli-Uzunbas G, Price SM, Chen GJ, Mathew R, et al. Autophagy sustains mitochondrial glutamine metabolism and growth of BrafV600E-driven lung tumors. Cancer Discov. 2013;3(11):1272-1285.
Not in our library10.1158/2159-8290.cd-13-0397
239.
Yang S, Wang X, Contino G, Liesa M, Sahin E, Ying H, et al. Pancreatic cancers require autophagy for tumor growth. Genes Dev. 2011;25(7):717-729.
Not in our library10.1101/gad.2016111
240.
Yang A, Rajeshkumar NV, Wang X, Yabuuchi S, Alexander BM, Chu GC, et al. Autophagy is critical for pancreatic tumor growth and progression in tumors with p53 alterations. Cancer Discov. 2014;4(8):905-913.
Not in our library10.1158/2159-8290.cd-14-0362
241.
Guo JY, Karsli-Uzunbas G, Mathew R, Aisner SC, Kamphorst JJ, Strohecker AM, et al. Autophagy suppresses progression of K-ras-induced lung tumors to oncocytomas and maintains lipid homeostasis. Genes Dev. 2013;27(13):1447-1461.
Not in our library10.1101/gad.219642.113
242.
Rao S, Tortola L, Perlot T, Wirnsberger G, Novatchkova M, Nitsch R, et al. A dual role for autophagy in a murine model of lung cancer. Nat Commun. 2014;5(1):3056.
Not in our library10.1038/ncomms4056
243.
Rosenfeldt MT, O'Prey J, Morton JP, Nixon C, MacKay G, Mrowinska A, et al. p53 status determines the role of autophagy in pancreatic tumour development. Nature. 2013;504(7479):296-300.
Not in our library10.1038/nature12865
244.
Yang A, Herter-Sprie G, Zhang H, Lin EY, Biancur D, Wang X, et al. Autophagy sustains pancreatic cancer growth through both cell-autonomous and nonautonomous mechanisms. Cancer Discov. 2018;8(3):276-287.
Not in our library10.1158/2159-8290.cd-17-0952
245.
Xie X, Koh JY, Price S, White E, Mehnert JM. Atg7 overcomes senescence and promotes growth of BrafV600E-driven melanoma. Cancer Discov. 2015;5(4):410-423.
Not in our library10.1158/2159-8290.cd-14-1473
246.
Amaravadi R, Kimmelman AC, White E. Recent insights into the function of autophagy in cancer. Genes Dev. 2016;30(17):1913-1930.
Not in our library10.1101/gad.287524.116
247.
Guo JY, Teng X, Laddha SV, Ma S, Van Nostrand SC, Yang Y, et al. Autophagy provides metabolic substrates to maintain energy charge and nucleotide pools in Ras-driven lung cancer cells. Genes Dev. 2016;30(15):1704-1717.
Not in our library10.1101/gad.283416.116
248.
Bryant KL, Stalnecker CA, Zeitouni D, Klomp JE, Peng S, Tikunov AP, et al. Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer. Nat Med. 2019;25(4):628-640.
Not in our library10.1038/s41591-019-0368-8
249.
Lee CS, Lee LC, Yuan TL, Chakka S, Fellmann C, Lowe SW, et al. MAP kinase and autophagy pathways cooperate to maintain RAS mutant cancer cell survival. Proc Natl Acad Sci U S A. 2019;116(10):4508-4517.
Not in our library10.1073/pnas.1817494116
250.
Egan DF, Shackelford DB, Mihaylova MM, Gelino S, Kohnz RA, Mair W, et al. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science. 2011;331(6016):456-461.
Not in our library10.1126/science.1196371
251.
Kim J, Kundu M, Viollet B, Guan KL. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol. 2011;13(2):132-141.
Not in our library10.1038/ncb2152
252.
Mihaylova MM, Shaw RJ. The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat Cell Biol. 2011;13(9):1016-1023.
Not in our library10.1038/ncb2329
253.
Sanduja S, Feng Y, Mathis RA, Sokol ES, Reinhardt F, Halaban R, et al. AMPK promotes tolerance to Ras pathway inhibition by activating autophagy. Oncogene. 2016;35(40):5295-5303.
Not in our library10.1038/onc.2016.70
254.
Kinsey CG, Camolotto SA, Boespflug AM, Guillen KP, Foth M, Truong A, et al. Protective autophagy elicited by RAF-->MEK-->ERK inhibition suggests a treatment strategy for RAS-driven cancers. Nat Med. 2019;25(4):620-627.
Not in our library10.1038/s41591-019-0367-9
255.
Hudis CA. Trastuzumab—mechanism of action and use in clinical practice. N Engl J Med. 2007;357(1):39-51.
Not in our library10.1056/nejmra043186
256.
Messersmith WA, Ahnen DJ. Targeting EGFR in colorectal cancer. N Engl J Med. 2008;359(17):1834-1836.
Not in our library10.1056/nejme0806778
257.
Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013;369(11):1023-1034.
Not in our library10.1056/nejmoa1305275
258.
Johnston S, Pippen J, Pivot X, Lichinitser M, Sadeghi S, Dieras V, et al. Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol. 2009;27(33):5538-5546.
Not in our library10.1200/jco.2009.23.3734
259.
Tripathy D, Slamon DJ, Cobleigh M, Arnold A, Saleh M, Mortimer JE, et al. Safety of treatment of metastatic breast cancer with trastuzumab beyond disease progression. J Clin Oncol. 2004;22(6):1063-1070.
Not in our library10.1200/jco.2004.06.557
260.
Montemurro F, Donadio M, Clavarezza M, Redana S, Jacomuzzi ME, Valabrega G, et al. Outcome of patients with HER2-positive advanced breast cancer progressing during trastuzumab-based therapy. Oncologist. 2006;11(4):318-324.
Not in our library10.1634/theoncologist.11-4-318
261.
Li D, Ambrogio L, Shimamura T, Kubo S, Takahashi M, Chirieac LR, et al. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene. 2008;27(34):4702-4711.
Not in our library10.1038/onc.2008.109
262.
Solca F, Dahl G, Zoephel A, Bader G, Sanderson M, Klein C, et al. Target binding properties and cellular activity of afatinib (BIBW 2992), an irreversible ErbB family blocker. J Pharmacol Exp Ther. 2012;343(2):342-350.
Not in our library10.1124/jpet.112.197756
263.
Schiering N, Knapp S, Marconi M, Flocco MM, Cui J, Perego R, et al. Crystal structure of the tyrosine kinase domain of the hepatocyte growth factor receptor c-Met and its complex with the microbial alkaloid K-252a. Proc Natl Acad Sci U S A. 2003;100(22):12654-12659.
Not in our library10.1073/pnas.1734128100
264.
Gysin S, Salt M, Young A, McCormick F. Therapeutic strategies for targeting ras proteins. Genes Cancer. 2011;2(3):359-372.
Not in our library10.1177/1947601911412376
265.
Li Z, Jiang K, Zhu X, Lin G, Song F, Zhao Y, et al. Encorafenib (LGX818), a potent BRAF inhibitor, induces senescence accompanied by autophagy in BRAFV600E melanoma cells. Cancer Lett. 2016;370(2):332-344.
Not in our library10.1016/j.canlet.2015.11.015
266.
Van Allen EM, Wagle N, Sucker A, Treacy DJ, Johannessen CM, Goetz EM, et al. The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma. Cancer Discov. 2014;4(1):94-109.
Not in our library10.1158/2159-8290.cd-13-0617
267.
Downward J. RAS synthetic lethal screens revisited: still seeking the elusive prize? Clin Cancer Res. 2015;21(8):1802-1809.
Not in our library10.1158/1078-0432.ccr-14-2180
268.
Scholl C, Frohling S, Dunn IF, Schinzel AC, Barbie DA, Kim SY, et al. Synthetic lethal interaction between oncogenic KRAS dependency and STK33 suppression in human cancer cells. Cell. 2009;137(5):821-834.
Not in our library10.1016/j.cell.2009.03.017
269.
Wang T, Yu H, Hughes NW, Liu B, Kendirli A, Klein K, et al. Gene essentiality profiling reveals gene networks and synthetic lethal interactions with oncogenic Ras. Cell. 2017;168(5):890-903.
Not in our library10.1016/j.cell.2017.01.013
270.
Anderson GR, Winter PS, Lin KH, Nussbaum DP, Cakir M, Stein EM, et al. A landscape of therapeutic cooperativity in KRAS mutant cancers reveals principles for controlling tumor evolution. Cell Rep. 2017;20(4):999-1015.
Not in our library10.1016/j.celrep.2017.07.006
271.
Martin TD, Cook DR, Choi MY, Li MZ, Haigis KM, Elledge SJ. A role for mitochondrial translation in promotion of viability in K-Ras mutant cells. Cell Rep. 2017;20(2):427-438.
Not in our library10.1016/j.celrep.2017.06.061
272.
Corcoran RB, Cheng KA, Hata AN, Faber AC, Ebi H, Coffee EM, et al. Synthetic lethal interaction of combined BCL-XL and MEK inhibition promotes tumor regressions in KRAS mutant cancer models. Cancer Cell. 2013;23(1):121-128.
Not in our library10.1016/j.ccr.2012.11.007
273.
Oncogene Mimicry as a Mechanism of Primary Resistance to BRAF Inhibitors · 2014
Not checked
274.
Haling JR, Sudhamsu J, Yen I, Sideris S, Sandoval W, Phung W, et al. Structure of the BRAF-MEK complex reveals a kinase activity independent role for BRAF in MAPK signaling. Cancer Cell. 2014;26(3):402-413.
Not in our library10.1016/j.ccr.2014.07.007
275.
Dumaz N, Hayward R, Martin J, Ogilvie L, Hedley D, Curtin JA, et al. In melanoma, RAS mutations are accompanied by switching signaling from BRAF to CRAF and disrupted cyclic AMP signaling. Cancer Res. 2006;66(19):9483-9491.
Not in our library10.1158/0008-5472.can-05-4227
276.
Cox AD, Der CJ. The raf inhibitor paradox: unexpected consequences of targeted drugs. Cancer Cell. 2010;17(3):221-223.
Not in our library10.1016/j.ccr.2010.02.029
277.
Kinase-Dead BRAF and Oncogenic RAS Cooperate to Drive Tumor Progression through CRAF · 2010
No notice
278.
Hatzivassiliou G, Song K, Yen I, Brandhuber BJ, Anderson DJ, Alvarado R, et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature. 2010;464(7287):431-435.
Not in our library10.1038/nature08833
279.
Aguirre AJ, Hahn WC. Synthetic lethal vulnerabilities in KRAS-mutant cancers. Cold Spring Harb Perspect Med. 2018;8(8):a031518.
Not in our library10.1101/cshperspect.a031518
280.
Sueda T, Sakai D, Kawamoto K, Konno M, Nishida N, Koseki J, et al. BRAF V600E inhibition stimulates AMP-activated protein kinase-mediated autophagy in colorectal cancer cells. Sci Rep. 2016;6:18949.
Not in our library10.1038/srep18949
281.
Peng SB, Henry JR, Kaufman MD, Lu WP, Smith BD, Vogeti S, et al. Inhibition of RAF isoforms and active dimers by LY3009120 leads to anti-tumor activities in RAS or BRAF mutant cancers. Cancer Cell. 2015;28(3):384-398.
Not in our library10.1016/j.ccell.2015.08.002
282.
Tutuka CSA, Andrews MC, Mariadason JM, Ioannidis P, Hudson C, Cebon J, et al. PLX8394, a new generation BRAF inhibitor, selectively inhibits BRAF in colonic adenocarcinoma cells and prevents paradoxical MAPK pathway activation. Mol Cancer. 2017;16(1):112.
Not in our library10.1186/s12943-017-0684-x
283.
Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001;108(8):1167-1174.
Not in our library10.1172/jci13505

Cited by papers we hold 11

Balancing between cuproplasia and copper-dependent cell death: molecular basis and clinical implications of ATOX1 in cancer · 2025
Not checked
Regulated cell death (RCD) in cancer: key pathways and targeted therapies · 2022
No notice
Elaiophylin triggers paraptosis and preferentially kills ovarian cancer drug-resistant cells by inducing MAPK hyperactivation · 2022
Not checked
Small molecule inhibitors targeting the cancers · 2022
No notice
Targeting regulated cell death (RCD) with small-molecule compounds in triple-negative breast cancer: a revisited perspective from molecular mechanisms to targeted therapies · 2022
No notice
Targeting the PI3K/AKT/mTOR and RAF/MEK/ERK pathways for cancer therapy · 2022
No notice
Molecular targeted therapy for anticancer treatment · 2022
No notice
Mitochondrial Effects on Seeds of Cancer Survival in Leukemia · 2021
Not checked
Regulation of PD-L1 expression in the tumor microenvironment · 2021
No notice
MAPK/ERK Signaling Pathway in Hepatocellular Carcinoma · 2021
No notice
Progress on Ras/MAPK Signaling Research and Targeting in Blood and Solid Cancers · 2021
No notice

Reads

Read by people on this page

None yet.

Checked or read by AI through naulon

None yet.

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

Are you an author?

Is this your paper?

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