MEK and the inhibitors: from bench to bedside

Four distinct MAP kinase signaling pathways involving 7 MEK enzymes have been identified. MEK1 and MEK2 are the prototype members of MEK family proteins. Several MEK inhibitors are in clinical trials. Trametinib is being evaluated by FDA for the treatment of metastatic melanoma with BRAF V600 mutation. Selumetinib has been studied in combination with docetaxel in phase II randomized trial in previously treated patients with advanced lung cancer. Selumetinib group had better response rate and progression-free survival. This review also summarized new MEK inhibitors in clinical development, including pimasertib, refametinib, PD-0325901, TAK733, MEK162 (ARRY 438162), RO5126766, WX-554, RO4987655 (CH4987655), GDC-0973 (XL518), and AZD8330.

[1]  Chen Yan,et al.  The Hinge-Helix 1 Region of Peroxisome Proliferator-Activated Receptor γ1 (PPARγ1) Mediates Interaction with Extracellular Signal-Regulated Kinase 5 and PPARγ1 Transcriptional Activation: Involvement in Flow-Induced PPARγ Activation in Endothelial Cells , 2004, Molecular and Cellular Biology.

[2]  J. Schellens,et al.  Phase I Dose-Escalation Study of the Safety, Pharmacokinetics, and Pharmacodynamics of the MEK Inhibitor RO4987655 (CH4987655) in Patients with Advanced Solid Tumors , 2012, Clinical Cancer Research.

[3]  M. Morgan,et al.  Selumetinib in women with recurrent low-grade serous carcinoma of the ovary or peritoneum: an open-label, single-arm, phase 2 study. , 2013, The Lancet. Oncology.

[4]  M. Gorospe,et al.  Targeted deletion of MKK4 in cancer cells: a detrimental phenotype manifests as decreased experimental metastasis and suggests a counterweight to the evolution of tumor-suppressor loss. , 2006, Cancer research.

[5]  J. Hainsworth,et al.  A Phase II, Open-Label, Randomized Study to Assess the Efficacy and Safety of AZD6244 (ARRY-142886) Versus Pemetrexed in Patients with Non-small Cell Lung Cancer Who Have Failed One or Two Prior Chemotherapeutic Regimens , 2010, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[6]  C. Berking,et al.  MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study. , 2013, The Lancet. Oncology.

[7]  Mark Merchant,et al.  Intermittent administration of MEK inhibitor GDC-0973 plus PI3K inhibitor GDC-0941 triggers robust apoptosis and tumor growth inhibition. , 2012, Cancer research.

[8]  H. Saito,et al.  Conserved docking site is essential for activation of mammalian MAP kinase kinases by specific MAP kinase kinase kinases. , 2005, Molecular cell.

[9]  D. Sacks.  The role of scaffold proteins in MEK/ERK signalling. , 2006, Biochemical Society transactions.

[10]  Chae Young Hwang,et al.  Extracellular Signal-Regulated Kinase 2-Dependent Phosphorylation Induces Cytoplasmic Localization and Degradation of p21Cip1 , 2009, Molecular and Cellular Biology.

[11]  R. Hamatake,et al.  RDEA119/BAY 869766: a potent, selective, allosteric inhibitor of MEK1/2 for the treatment of cancer. , 2009, Cancer research.

[12]  Gaochao Zhou,et al.  Components of a New Human Protein Kinase Signal Transduction Pathway (*) , 1995, The Journal of Biological Chemistry.

[13]  A. Rosenwald,et al.  Comprehensive analysis of homeobox genes in Hodgkin lymphoma cell lines identifies dysregulated expression of HOXB9 mediated via ERK5 signaling and BMI1. , 2007, Blood.

[14]  T. Hunter,et al.  The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. , 1988, Science.

[15]  Suzanne F. Jones,et al.  Abstract B243: A phase I dose-escalation study of MEK inhibitor MEK162 (ARRY-438162) in patients with advanced solid tumors. , 2011 .

[16]  K. Flaherty,et al.  Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial. , 2012, The Lancet. Oncology.

[17]  G. Mills,et al.  ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation , 2008, Nature Cell Biology.

[18]  R. Dummer,et al.  Phase II, Open-Label, Randomized Trial of the MEK1/2 Inhibitor Selumetinib as Monotherapy versus Temozolomide in Patients with Advanced Melanoma , 2011, Clinical Cancer Research.

[19]  V. Velculescu,et al.  Homozygous deletion of MKK4 in ovarian serous carcinoma , 2006, Cancer biology & therapy.

[20]  R. Tapping,et al.  MEKK3 Directly Regulates MEK5 Activity as Part of the Big Mitogen-activated Protein Kinase 1 (BMK1) Signaling Pathway* , 1999, The Journal of Biological Chemistry.

[21]  Thomas Efferth,et al.  Polo-like kinase 1 as target for cancer therapy , 2012, Experimental Hematology & Oncology.

[22]  A. Hauschild,et al.  Improved survival with vemurafenib in melanoma with BRAF V600E mutation. , 2011, The New England journal of medicine.

[23]  J. Abe,et al.  The hinge-helix 1 region of peroxisome proliferator-activated receptor gamma1 (PPARgamma1) mediates interaction with extracellular signal-regulated kinase 5 and PPARgamma1 transcriptional activation: involvement in flow-induced PPARgamma activation in endothelial cells. , 2004, Molecular and cellular biology.

[24]  C. Tournier,et al.  Regulation of cellular functions by the ERK5 signalling pathway. , 2006, Cellular signalling.

[25]  Takayuki Yamaguchi,et al.  Antitumor activities of JTP-74057 (GSK1120212), a novel MEK1/2 inhibitor, on colorectal cancer cell lines in vitro and in vivo. , 2011, International journal of oncology.

[26]  Jiahuai Han,et al.  Activation and signaling of the p38 MAP kinase pathway , 2005, Cell Research.

[27]  J. Lyons,et al.  Recent progress in targeting the Raf/MEK/ERK pathway with inhibitors in cancer drug discovery. , 2005, Current opinion in pharmacology.

[28]  Fengqin Gao,et al.  Novel Role for JNK as a Stress-activated Bcl2 Kinase* , 2001, The Journal of Biological Chemistry.

[29]  J. Warmus,et al.  The Discovery of the Benzhydroxamate MEK Inhibitors CI‐1040 and PD 0325901. , 2009 .

[30]  T. Ciuleanu,et al.  A phase II open-label randomized study to assess the efficacy and safety of selumetinib (AZD6244 [ARRY-142886]) versus capecitabine in patients with advanced or metastatic pancreatic cancer who have failed first-line gemcitabine therapy , 2012, Investigational New Drugs.

[31]  M. Cobb,et al.  Identification of Substrates and Regulators of the Mitogen-activated Protein Kinase ERK5 Using Chimeric Protein Kinases* , 1998, The Journal of Biological Chemistry.

[32]  Kang-Yell Choi,et al.  MEK1/2 inhibitors AS703026 and AZD6244 may be potential therapies for KRAS mutated colorectal cancer that is resistant to EGFR monoclonal antibody therapy. , 2011, Cancer research.

[33]  Y. Ip,et al.  Signal transduction by the c-Jun N-terminal kinase (JNK)--from inflammation to development. , 1998, Current opinion in cell biology.

[34]  T. Liu,et al.  A full-length 3D structure for MAPK/ERK kinase 2 (MEK2) , 2011, Science China Life Sciences.

[35]  G. Pellacani,et al.  Overwhelming response to Dabrafenib in a patient with double BRAF mutation (V600E; V600M) metastatic malignant melanoma , 2012, Journal of Hematology & Oncology.

[36]  M. Belvin,et al.  Bridging the Gap between Preclinical and Clinical Studies Using Pharmacokinetic–Pharmacodynamic Modeling: An Analysis of GDC-0973, a MEK Inhibitor , 2012, Clinical Cancer Research.

[37]  J. Lyssikatos,et al.  Progress towards therapeutic small molecule MEK inhibitors for use in cancer therapy. , 2005, Current topics in medicinal chemistry.

[38]  Hong Wang,et al.  MicroRNAs and Toll-like Receptor/Interleukin-1 Receptor Signaling , 2012, Journal of Hematology & Oncology.

[39]  Jiahuai Han,et al.  Characterization of the Structure and Function of a Novel MAP Kinase Kinase (MKK6) (*) , 1996, The Journal of Biological Chemistry.

[40]  M. Belvin,et al.  Preclinical Disposition of GDC-0973 and Prospective and Retrospective Analysis of Human Dose and Efficacy Predictions , 2012, Drug Metabolism and Disposition.

[41]  F. Rojo,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 , 2012, Clinical Cancer Research.

[42]  Wei Guo,et al.  Characterization of the Structure and Function of a New Mitogen-activated Protein Kinase (p38β)* , 1996, The Journal of Biological Chemistry.

[43]  W. Franklin,et al.  Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[44]  Vivienne Marsh,et al.  Biological Characterization of ARRY-142886 (AZD6244), a Potent, Highly Selective Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor , 2007, Clinical Cancer Research.

[45]  Delong Liu,et al.  Dysregulation of JAK-STAT pathway in hematological malignancies and JAK inhibitors for clinical application , 2013, Biomarker Research.

[46]  Eugene M. Johnson,et al.  JNK-Mediated BIM Phosphorylation Potentiates BAX-Dependent Apoptosis , 2003, Neuron.

[47]  Wei Li,et al.  Erk5 null mice display multiple extraembryonic vascular and embryonic cardiovascular defects , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[48]  Li Ding,et al.  Novel MEK1 mutation identified by mutational analysis of epidermal growth factor receptor signaling pathway genes in lung adenocarcinoma. , 2008, Cancer research.

[49]  G. Lanfranchi,et al.  Chromosomal localization of four MAPK signaling cascade genes: MEK1, MEK3, MEK4 and MEKK5. , 1997, Cytogenetics and cell genetics.

[50]  Jingwu Xie,et al.  MEK1 mutations, but not ERK2 mutations, occur in melanomas and colon carcinomas, but none in thyroid carcinomas , 2009, Cell cycle.

[51]  A. Winoto,et al.  ERK5 Is a Novel Type of Mitogen-Activated Protein Kinase Containing a Transcriptional Activation Domain , 2000, Molecular and Cellular Biology.

[52]  P. Xu,et al.  c-Jun NH2-Terminal Kinase Is Required for Lineage-Specific Differentiation but Not Stem Cell Self-Renewal , 2010, Molecular and Cellular Biology.

[53]  Abstract C197: A phase 1 safety and pharmacokinetic (PK) study of the PI3K inhibitor XL147 (SAR245408) in combination with erlotinib in patients with advanced solid tumors , 2009 .

[54]  D. V. Von Hoff,et al.  Safety, pharmacokinetics, and pharmacodynamics results from a phase I trial of BAY 86-9766 (RDEA119), a MEK inhibitor, in patients with advanced cancer. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[55]  R. Assoian,et al.  Integrating the MAP kinase signal into the G1 phase cell cycle machinery. , 2000, BioEssays : news and reviews in molecular, cellular and developmental biology.

[56]  D. Bar-Sagi,et al.  Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway. , 2000, Science.

[57]  A. Bridges,et al.  The biological profile of PD 0325901: A second generation analog of CI-1040 with improved pharmaceutical potential , 2004 .

[58]  Suzanne F. Jones,et al.  Abstract B128: A phase IB study of the MEK inhibitor GSK1120212 combined with everolimus in patients with solid tumors: Interim results. , 2011 .

[59]  C. Lukacs,et al.  Design and synthesis of novel allosteric MEK inhibitor CH4987655 as an orally available anticancer agent. , 2011, Bioorganic & medicinal chemistry letters.

[60]  Tae-You Kim,et al.  A Phase II, open-label, randomised study to assess the efficacy and safety of the MEK1/2 inhibitor AZD6244 (ARRY-142886) versus capecitabine monotherapy in patients with colorectal cancer who have failed one or two prior chemotherapeutic regimens , 2011, Investigational New Drugs.

[61]  A. Nicholson,et al.  Mutations of the BRAF gene in human cancer , 2002, Nature.

[62]  D. Huo,et al.  The p38 kinases MKK4 and MKK6 suppress metastatic colonization in human ovarian carcinoma. , 2006, Cancer research.

[63]  Lucio Crinò,et al.  Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study. , 2013, The Lancet. Oncology.

[64]  J. Guerrero,et al.  Regulation of cardiac hypertrophy in vivo by the stress-activated protein kinases/c-Jun NH(2)-terminal kinases. , 1999, The Journal of clinical investigation.

[65]  Delong Liu,et al.  Current management and prognostic features for gastrointestinal stromal tumor (GIST) , 2012, Experimental Hematology & Oncology.

[66]  E. Nishida,et al.  Requirement of the MEK5–ERK5 pathway for neural differentiation in Xenopus embryonic development , 2005, EMBO reports.

[67]  A. Fornace,et al.  p38 MAP kinase's emerging role as a tumor suppressor. , 2004, Advances in cancer research.

[68]  Lihong Shi,et al.  Discovery of TAK-733, a potent and selective MEK allosteric site inhibitor for the treatment of cancer. , 2011, Bioorganic & medicinal chemistry letters.

[69]  D. Young,et al.  Cloning and Characterization of MEK6, a Novel Member of the Mitogen-activated Protein Kinase Kinase Cascade (*) , 1996, The Journal of Biological Chemistry.

[70]  G. Clayman,et al.  MEK Inhibitor PD0325901 Significantly Reduces the Growth of Papillary Thyroid Carcinoma Cells In vitro and In vivo , 2010, Molecular Cancer Therapeutics.

[71]  S. Aamdal,et al.  A phase I dose-finding, safety and tolerability study of AZD8330 in patients with advanced malignancies. , 2013, European journal of cancer.

[72]  Jiahuai Han,et al.  BMK1/ERK5 regulates serum‐induced early gene expression through transcription factor MEF2C , 1997, The EMBO journal.

[73]  D. Hedley,et al.  Antitumour activity of a potent MEK inhibitor RDEA119/BAY 869766 combined with rapamycin in human orthotopic primary pancreatic cancer xenografts , 2010, BMC Cancer.

[74]  M. Karin,et al.  Identification of a dual specificity kinase that activates the Jun kinases and p38-Mpk2. , 1995, Science.

[75]  M. Karin,et al.  Mammalian MAP kinase signalling cascades , 2001, Nature.

[76]  R. Finn,et al.  A phase I study of MEK inhibitor MEK162 (ARRY-438162) in patients with biliary tract cancer. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[77]  E. Gelfand,et al.  MEKK2 Associates with the Adapter Protein Lad/RIBP and Regulates the MEK5-BMK1/ERK5 Pathway* , 2001, The Journal of Biological Chemistry.

[78]  Delong Liu,et al.  Current management and novel agents for malignant melanoma , 2012, Journal of Hematology & Oncology.

[79]  J. Utikal,et al.  Improved survival with MEK inhibition in BRAF-mutated melanoma. , 2012, The New England journal of medicine.

[80]  E. Appella,et al.  Initiation of a G2/M checkpoint after ultraviolet radiation requires p38 kinase , 2001, Nature.

[81]  K. Rau,et al.  A phase II trial of MEK inhibitor BAY 86-9766 in combination with sorafenib as first-line systemic treatment for patients with unresectable hepatocellular carcinoma (HCC). , 2012 .

[82]  Francesca Zappacosta,et al.  GSK1120212 (JTP-74057) Is an Inhibitor of MEK Activity and Activation with Favorable Pharmacokinetic Properties for Sustained In Vivo Pathway Inhibition , 2011, Clinical Cancer Research.

[83]  Dirk Schadendorf,et al.  Improved survival with MEK Inhibition in BRAF-mutated melanoma for the METRIC Study Group , 2012 .

[84]  J. Avruch,et al.  Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. , 2001, Physiological reviews.

[85]  Ruey-min Lee,et al.  Phase II study of the mitogen-activated protein kinase 1/2 inhibitor selumetinib in patients with advanced hepatocellular carcinoma. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[86]  D. Neal,et al.  MEK5 overexpression is associated with metastatic prostate cancer, and stimulates proliferation, MMP-9 expression and invasion , 2003, Oncogene.

[87]  Expression of the phosphorylated MEK5 protein is associated with TNM staging of colorectal cancer , 2012, BMC Cancer.

[88]  H. Pass,et al.  HGF mediates cell proliferation of human mesothelioma cells through a PI3K/MEK5/Fra-1 pathway. , 2008, American journal of respiratory cell and molecular biology.

[89]  Hong Wang,et al.  Novel biomarkers for diagnosis, prognosis, targeted therapy and clinical trials , 2013, Biomarker Research.

[90]  P. Crespo,et al.  Erk5 Participates in Neuregulin Signal Transduction and Is Constitutively Active in Breast Cancer Cells Overexpressing ErbB2 , 2002, Molecular and Cellular Biology.

[91]  Shuang Huang,et al.  Bmk1/Erk5 is required for cell proliferation induced by epidermal growth factor , 1998, Nature.

[92]  N. Munshi,et al.  Blockade of the MEK/ERK signalling cascade by AS703026, a novel selective MEK1/2 inhibitor, induces pleiotropic anti‐myeloma activity in vitro and in vivo , 2010, British journal of haematology.

[93]  M. Cobb,et al.  Isolation of MEK5 and Differential Expression of Alternatively Spliced Forms * , 1995, The Journal of Biological Chemistry.

[94]  D. Bar-Sagi,et al.  RAS oncogenes: weaving a tumorigenic web , 2011, Nature Reviews Cancer.

[95]  E. Wagner,et al.  Liver Tumor Development c-Jun Antagonizes the Proapoptotic Activity of p53 , 2003, Cell.

[96]  Eric B Haura,et al.  A Phase II Study of PD-0325901, an Oral MEK Inhibitor, in Previously Treated Patients with Advanced Non–Small Cell Lung Cancer , 2010, Clinical Cancer Research.

[97]  J. Tabernero,et al.  PD-0024 Phase I/II Study of Folfiri Plus the MEK1/2 Inhibitor Pimasertib (MSC1936369B) as Second-Line Treatment for KRAS Mutated Metastatic Colorectal Cancer , 2012 .

[98]  Yuqi Liu,et al.  Fully activated MEK1 exhibits compromised affinity for binding of allosteric inhibitors U0126 and PD0325901. , 2011, Biochemistry.

[99]  L. Zon,et al.  SEK1 deficiency reveals mitogen-activated protein kinase cascade crossregulation and leads to abnormal hepatogenesis. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[100]  D. Hayes,et al.  Phase II Efficacy and Pharmacogenomic Study of Selumetinib (AZD6244; ARRY-142886) in Iodine-131 Refractory Papillary Thyroid Carcinoma with or without Follicular Elements , 2012, Clinical Cancer Research.

[101]  S. Larson,et al.  Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. , 2013, The New England journal of medicine.

[102]  Jiahuai Han,et al.  Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms , 1995, Science.

[103]  N. Hayashi,et al.  Involvement of the p38 mitogen‐activated protein kinase cascade in hepatocellular carcinoma , 2003, Cancer.

[104]  K. Hahn,et al.  PB1 Domain-Dependent Signaling Complex Is Required for Extracellular Signal-Regulated Kinase 5 Activation , 2006, Molecular and Cellular Biology.

[105]  P. LoRusso,et al.  Phase I and pharmacodynamic study of the oral MEK inhibitor CI-1040 in patients with advanced malignancies. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[106]  E. Nishida,et al.  Activation of the Protein Kinase ERK5/BMK1 by Receptor Tyrosine Kinases , 1999, The Journal of Biological Chemistry.

[107]  M. Belvin,et al.  A first-in-human phase Ib study to evaluate the MEK inhibitor GDC-0973, combined with the pan-PI3K inhibitor GDC-0941, in patients with advanced solid tumors. , 2012 .

[108]  Paul Reichert,et al.  Crystal structures of MEK1 binary and ternary complexes with nucleotides and inhibitors. , 2009, Biochemistry.

[109]  T. Mak,et al.  Impaired CD28-mediated Interleukin 2 Production and Proliferation in Stress Kinase SAPK/ERK1 Kinase (SEK1)/Mitogen-activated Protein Kinase Kinase 4 (MKK4)-deficient T Lymphocytes , 1997, The Journal of experimental medicine.

[110]  Y Taya,et al.  Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability. , 2000, Genes & development.

[111]  R. Roskoski,et al.  RAF protein-serine/threonine kinases: structure and regulation. , 2010, Biochemical and biophysical research communications.

[112]  Nobuyuki Tanaka,et al.  Mechanism of p38 MAP kinase activation in vivo. , 2003, Genes & development.

[113]  S. Cook,et al.  Tumour cell survival signalling by the ERK1/2 pathway , 2009, Cell Death and Differentiation.

[114]  E. Nishida,et al.  Regulation of c‐Fos and Fra‐1 by the MEK5‐ERK5 pathway , 2003, Genes to cells : devoted to molecular & cellular mechanisms.

[115]  A. Ribas,et al.  Antitumor effects of the investigational selective MEK inhibitor TAK733 against cutaneous and uveal melanoma cell lines , 2012, Molecular Cancer.