The mitogen-activated extracellular signal-regulated kinase (MEK) pathway is one of the best-characterized kinase cascades in cancer cell biology. It is triggered by either growth factors or activating mutations of major oncogenic proteins in this pathway, the most common being Ras and Raf. Deregulation of this pathway is frequently observed and plays a central role in the carcinogenesis and maintenance of several cancers, including melanoma, pancreatic, lung, colorectal, and breast cancers. Targeting these kinases offers promise of novel therapies. MEK inhibitors (MEKi) are currently under evaluation in clinical trials and many have shown activity. In this review, we comprehensively examine the role of the MEK pathway in carcinogenesis and its therapeutic potential in cancer patients, with a focus on MEKi. We describe the clinical perspectives of MEKi in the two main models of Ras-ERK driven tumors, BRAF-mutant ("addicted" to the pathway) and KRAS-mutant (non-"addicted"). We also highlight the known mechanisms of resistance to MEKi and emerging strategies to overcome it.
Activation of mitogen-activated protein kinases/extracellular signal-regulated kinases in human hepatocellular carcinoma
Hepatitis C virus core protein activates the MAPK/ERK cascade synergistically with tumor promoter TPA, but not with epidermal growth factor or transforming growth factor alpha
Sustained activation of the Raf/MEK/Erk pathway in response to EGF in stable cell lines expressing the Hepatitis C Virus (HCV) core protein
PAK1 primes MEK1 for phosphorylation by Raf-1 kinase during cross-cascade activation of the ERK pathway
UCN-01-induced cell cycle arrest requires the transcriptional induction of p21(waf1/cip1) by activation of mitogen-activated protein/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase pathway
Multicenter phase II study of the oral MEK inhibitor, CI-1040, in patients with advanced non-small-cell lung, breast, colon, and pancreatic cancer
Pharmacologic inhibition of RAF-->MEK-->ERK signaling elicits pancreatic cancer cell cycle arrest through induced expression of p27Kip1
Phase I and pharmacodynamic study of the oral MEK inhibitor CI-1040 in patients with advanced malignancies
Involvement of MMP-7 in invasion of pancreatic cancer cells through activation of the EGFR mediated MEK-ERK signal transduction pathway
Activation of the ERK and AKT signalling pathway predicts poor prognosis in hepatocellular carcinoma and ERK activation in cancer tissue is associated with hepatitis C virus infection
Basal subtype and MAPK/ERK kinase (MEK)-phosphoinositide 3-kinase feedback signaling determine susceptibility of breast cancer cells to MEK inhibition
KRAS/BRAF mutation status and ERK1/2 activation as biomarkers for MEK1/2 inhibitor therapy in colorectal cancer
In vivo antitumor activity of MEK and phosphatidylinositol 3-kinase inhibitors in basal-like breast cancer models
Intrinsic resistance to the MEK1/2 inhibitor AZD6244 (ARRY-142886) is associated with weak ERK1/2 signalling and/or strong PI3K signalling in colorectal cancer cell lines
Identifying genotype-dependent efficacy of single and combined PI3K- and MAPK-pathway inhibition in cancer
PD0325901, a mitogen-activated protein kinase kinase inhibitor, produces ocular toxicity in a rabbit animal model of retinal vein occlusion
Effects of combined inhibition of MEK and mTOR on downstream signaling and tumor growth in pancreatic cancer xenograft models
The complex interplay between ERK1/2, TGFβ/Smad, and Jagged/Notch signaling pathways in the regulation of epithelial-mesenchymal transition in retinal pigment epithelium cells
Hydroxysafflor yellow A inhibits angiogenesis of hepatocellular carcinoma via blocking ERK/MAPK and NF-κB signaling pathway in H22 tumor-bearing mice
Filamin A expression correlates with proliferation and invasive properties of human metastatic melanoma tumors: implications for survival in patients
Sensitive methods for screening of the MEK1 gene mutations in patients with central nervous system metastases of non-small cell lung cancer
Astrocyte elevated gene-1 regulates CCL3/CCR5-induced epithelial-to-mesenchymal transition via Erk1/2 and Akt signaling in cardiac myxoma
PI3K/Akt/mTOR and Ras/Raf/MEK/ERK signaling pathways inhibitors as anticancer agents: Structural and pharmacological perspectives
Cytotoxicity of PEGylated liposomes co-loaded with novel pro-apoptotic drug NCL-240 and the MEK inhibitor cobimetinib against colon carcinoma in vitro
From gene discovery to new biological mechanisms: heparanases and congenital urinary bladder disease
Mitogen-activated protein kinases and Hedgehog-GLI signaling in cancer: A crosstalk providing therapeutic opportunities?
Melanoma cell-derived exosomes promote epithelial-mesenchymal transition in primary melanocytes through paracrine/autocrine signaling in the tumor microenvironment
C23 protein meditates bone morphogenetic protein-2-mediated EMT via up-regulation of Erk1/2 and Akt in gastric cancer
CCL18 promotes the invasion and migration of gastric cancer cells via ERK1/2/NF-κB signaling pathway
Towards pathway-centric cancer therapies via pharmacogenomic profiling analysis of ERK signalling pathway
Galectin-1 induces hepatocellular carcinoma EMT and sorafenib resistance by activating FAK/PI3K/AKT signaling
Mechanistic studies of cancer cell mitochondria- and NQO1-mediated redox activation of beta-lapachone, a potentially novel anticancer agent
Actin cytoskeleton organization, cell surface modification and invasion rate of 5 glioblastoma cell lines differing in PTEN and p53 status
The tyrosine kinase inhibitor nilotinib has antineoplastic activity in prostate cancer cells but up-regulates the ERK survival signal-Implications for targeted therapies
mTORC1 upregulation via ERK-dependent gene expression change confers intrinsic resistance to MEK inhibitors in oncogenic KRas-mutant cancer cells
Retinal Toxicity Associated With MEK Inhibitor Use for Metastatic Cancer: A Rising Trend in Ophthalmology
Activating KRAS mutations are characteristic of oncocytic sinonasal papilloma and associated sinonasal squamous cell carcinoma
Clinicopathological and prognostic significance of mitogen-activated protein kinases (MAPK) in breast cancers
Pioglitazone induces cell growth arrest and activates mitochondrial apoptosis in human uterine leiomyosarcoma cells by a peroxisome proliferator-activated receptor γ-independent mechanism
Altered expression of autophagy-related genes might contribute to glucocorticoid resistance in precursor B-cell-type acute lymphoblastic leukemia
Trametinib plus 4-Methylumbelliferone Exhibits Antitumor Effects by ERK Blockade and CD44 Downregulation and Affects PD-1 and PD-L1 in Malignant Pleural Mesothelioma
Unravelling the pharmacologic opportunities and future directions for targeted therapies in gastro-intestinal cancers Part 1: GI carcinomas
Actin stress fiber organization promotes cell stiffening and proliferation of pre-invasive breast cancer cells
The MEK-Inhibitor Selumetinib Attenuates Tumor Growth and Reduces IL-6 Expression but Does Not Protect against Muscle Wasting in Lewis Lung Cancer Cachexia
A transcriptional MAPK Pathway Activity Score (MPAS) is a clinically relevant biomarker in multiple cancer types
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