Prospects for MEK inhibitors for treating cancer

Bibliography

• McCubrey JA, Steelman LS, Chappell WH, et al. Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta 2007;1773(8):1263-84
   PubMed Web of Science ®Google Scholar
• Chang L, Karin M. Mammalian MAP kinase signalling cascades. Nature 2001;410(6824):37-40
   PubMed Web of Science ®Google Scholar
• Cooper GM. Cellular transforming genes. Science 1982;217(4562):801-6
   PubMed Web of Science ®Google Scholar
• Santos E, Tronick SR, Aaronson SA, et al. T24 human bladder carcinoma oncogene is an activated form of the normal human homologue of BALB- and Harvey-MSV transforming genes. Nature 1982;298(5872):343-7
   PubMed Web of Science ®Google Scholar
• Parada LF, Tabin CJ, Shih C, et al. Human EJ bladder carcinoma oncogene is homologue of Harvey sarcoma virus ras gene. Nature 1982;297(5866):474-8
   PubMed Web of Science ®Google Scholar
• Santarpia L, Lippman SM, El-Naggar AK. Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy. Expert Opin Ther Targets 2012;16(1):103-19
   PubMed Web of Science ®Google Scholar
• Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature 2002;417(6892):949-54
   PubMed Web of Science ®Google Scholar
• Khattak M, Fisher R, Turajlic S, et al. Targeted therapy and immunotherapy in advanced melanoma: an evolving paradigm. Ther Adv Med Oncol 2013;5(2):105-18
   PubMed Web of Science ®Google Scholar
• Chapman P, Hauschild A, Robert C, et al. Updated overall survival (OS) results for BRIM-3, a phase III randomized, open-label, multicenter trial comparing BRAF inhibitor vemurafenib (vem) with dacarbazine (DTIC) in previously untreated patients with BRAFV600E-mutated melanoma. J Clin Oncol 2012;30(Suppl):abstract 8502
   Google Scholar
• Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 2012;367(2):107-14
   PubMed Web of Science ®Google Scholar
• Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 2012;367(18):1694-703
   PubMed Web of Science ®Google Scholar
• Available from: http://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm354478.htm
   Google Scholar
• Zimmer L, Vaubel J, Livingstone E, et al. Side effects of systemic oncological therapies in dermatology. J Dtsch Dermatol Ges 2012;10(7):475-86
   PubMed Web of Science ®Google Scholar
• Díez D, Sánchez-Jiménez F, Ranea JA. Evolutionary expansion of the Ras switch regulatory module in eukaryotes. Nucleic Acids Res 2011;39(13):5526-37
   PubMed Web of Science ®Google Scholar
• Crews CM, Alessandrini A, Erikson RL. The primary structure of MEK, a protein kinase that phosphorylates the ERK gene product. Science 1992;258(5081):478-80
   PubMed Web of Science ®Google Scholar
• Meloche S, Pouysségur J. The ERK1/2 mitogen-activated protein kinase pathway as a master regulator of the G1- to S-phase transition. Oncogene 2007;26(22):3227-39
   PubMed Web of Science ®Google Scholar
• Mebratu Y, Tesfaigzi Y. How ERK1/2 activation controls cell proliferation and cell death: Is subcellular localization the answer? Cell Cycle 2009;8(8):1168-75
   PubMed Web of Science ®Google Scholar
• Roskoski R. RAF protein-serine/threonine kinases: structure and regulation. Biochem Biophys Res Commun 2010;399(3):313-17
   PubMed Web of Science ®Google Scholar
• Jakob JA, Bassett RL, Ng CS, et al. NRAS mutation status is an independent prognostic factor in metastatic melanoma. Cancer 2012;118(16):4014-23
   PubMed Web of Science ®Google Scholar
• Cros J, Sbidian E, Hans S, et al. Expression and mutational status of treatment-relevant targets and key oncogenes in 123 malignant salivary gland tumours. Ann Oncol 2013;24(10):2624-9
   PubMed Web of Science ®Google Scholar
• Santarpia L, Myers JN, Sherman SI, et al. Genetic alterations in the RAS/RAF/mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt signaling pathways in the follicular variant of papillary thyroid carcinoma. Cancer 2010;116(12):2974-83
   PubMed Web of Science ®Google Scholar
• Vasko V, Ferrand M, Di Cristofaro J, et al. Specific pattern of RAS oncogene mutations in follicular thyroid tumors. J Clin Endocrinol Metab 2003;88(6):2745-52
   PubMed Web of Science ®Google Scholar
• Volante M, Rapa I, Gandhi M, et al. RAS mutations are the predominant molecular alteration in poorly differentiated thyroid carcinomas and bear prognostic impact. J Clin Endocrinol Metab 2009;94(12):4735-41
   PubMed Web of Science ®Google Scholar
• Tiacci E, Trifonov V, Schiavoni G, et al. BRAF mutations in hairy-cell leukemia. N Engl J Med 2011;364(24):2305-15
   PubMed Web of Science ®Google Scholar
• Burger JA. BRAF mutation: supporting diversity in HCL. Blood 2012;119(14):3193-4
   PubMed Web of Science ®Google Scholar
• Long GV, Menzies AM, Nagrial AM, et al. Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol 2011;29(10):1239-46
   PubMed Web of Science ®Google Scholar
• Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364(26):2507-16
   PubMed Web of Science ®Google Scholar
• Akinleye A, Furqan M, Mukhi N, et al. MEK and the inhibitors: from bench to bedside. J Hematol Oncol 2013;6:27
   PubMed Web of Science ®Google Scholar
• Marks JL, Gong Y, Chitale D, et al. Novel MEK1 mutation identified by mutational analysis of epidermal growth factor receptor signaling pathway genes in lung adenocarcinoma. Cancer Res 2008;68(14):5524-8
   PubMed Web of Science ®Google Scholar
• Murugan AK, Dong J, Xie J, et al. MEK1 mutations, but not ERK2 mutations, occur in melanomas and colon carcinomas, but none in thyroid carcinomas. Cell Cycle 2009;8(13):2122-4
   PubMed Web of Science ®Google Scholar
• Gilmartin AG, Bleam MR, Groy A, et al. GSK1120212 (JTP-74057) is an inhibitor of MEK activity and activation with favorable pharmacokinetic properties for sustained in vivo pathway inhibition. Clin Cancer Res 2011;17(5):989-1000
   PubMed Web of Science ®Google Scholar
• Infante JR, Fecher LA, Falchook GS, et al. Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial. Lancet Oncol 2012;13(8):773-81
   PubMed Web of Science ®Google Scholar
• Kim KB, Kefford R, Pavlick AC, et al. Phase II study of the MEK1/MEK2 inhibitor Trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor. J Clin Oncol 2013;31(4):482-9
   PubMed Web of Science ®Google Scholar
• Blumenschein GR, Smit EF, Planchard D, et al. MEK114653: A randomized, multicenter, phase II study to assess efficacy and safety of trametinib (T) compared with docetaxel (D) in KRAS-mutant advanced non–small cell lung cancer (NSCLC). J Clin Oncol 2013;31(Suppl):abstract 8029
   Google Scholar
• Falchook GS, Lewis KD, Infante JR, et al. Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial. Lancet Oncol 2012;13(8):782-9
   PubMed Web of Science ®Google Scholar
• Available from: http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm381451.htm
   Google Scholar
• Corcoran RB, Falchook GS, Infante JR, et al. Pharmacodynamic and efficacy analysis of the BRAF inhibitor dabrafenib (GSK436) in combination with the MEK inhibitor trametinib (GSK212) in patients with BRAFV600 mutant colorectal cancer (CRC). J Clin Oncol 2013;31(Suppl):abstract 3507
   Google Scholar
• Infante JR, Papadopoulos KP, Bendell JC, et al. A phase 1b study of trametinib, an oral Mitogen-activated protein kinase kinase (MEK) inhibitor, in combination with gemcitabine in advanced solid tumours. Eur J Cancer 2013. [ Epub ahead of print]
   Google Scholar
• Infante JR, Somer BG, Park JO, et al. A randomized, double-blind, placebo-controlled trial of trametinib, a MEK inhibitor, in combination with gemcitabine for patients with untreated metastatic adenocarcinoma of the pancreas. J Clin Oncol 2012;30(Suppl 34):abstract 291
   Google Scholar
• Kelly K, Mazieres J, Leighl NB, et al. Oral MEK1/MEK2 inhibitor trametinib (GSK1120212) in combination with pemetrexed for KRAS-mutant and wild-type (WT) advanced non-small cell lung cancer (NSCLC): a phase I/Ib trial. J Clin Oncol 2013;31(Suppl):abstract 8027
   Google Scholar
• Gandara DR, Hiret S, Blumenschein GR, et al. Oral MEK1/MEK2 inhibitor trametinib (GSK1120212) in combination with docetaxel in KRAS-mutant and wild-type (WT) advanced non-small cell lung cancer (NSCLC): a phase I/Ib trial. J Clin Oncol 2013;31(Suppl):abstract 8028
   Google Scholar
• Becerra C, Infante JR, Garbo LE, et al. A five-arm, open-label, phase I/lb study to assess safety and tolerability of the oral MEK1/MEK2 inhibitor trametinib (GSK1120212) in combination with chemotherapy or erlotinib in patients with advanced solid tumors. J Clin Oncol 2012;30(Suppl):abstract 3023
   Google Scholar
• Yeh TC, Marsh V, Bernat BA, et al. Biological characterization of ARRY-142886 (AZD6244), a potent, highly selective mitogen-activated protein kinase kinase 1/2 inhibitor. Clin Cancer Res 2007;13(5):1576-83
   PubMed Web of Science ®Google Scholar
• Adjei AA, Cohen RB, Franklin W, 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. J Clin Oncol 2008;26(13):2139-46
   PubMed Web of Science ®Google Scholar
• Bennouna J, Lang I, Valladares-Ayerbes M, 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. Invest New Drugs 2011;29(5):1021-8
   PubMed Web of Science ®Google Scholar
• Bodoky G, Timcheva C, Spigel DR, 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. Invest New Drugs 2012;30(3):1216-23
   PubMed Web of Science ®Google Scholar
• Hainsworth JD, Cebotaru CL, Kanarev V, 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. J Thorac Oncol 2010;5(10):1630-6
   PubMed Web of Science ®Google Scholar
• Hayes DN, Lucas AS, Tanvetyanon T, 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. Clin Cancer Res 2012;18(7):2056-65
   PubMed Web of Science ®Google Scholar
• O'Neil BH, Goff LW, Kauh JS, et al. Phase II study of the mitogen-activated protein kinase 1/2 inhibitor selumetinib in patients with advanced hepatocellular carcinoma. J Clin Oncol 2011;29(17):2350-6
   PubMed Web of Science ®Google Scholar
• Kirkwood JM, Bastholt L, Robert C, et al. Phase II, open-label, randomized trial of the MEK1/2 inhibitor selumetinib as monotherapy versus temozolomide in patients with advanced melanoma. Clin Cancer Res 2012;18(2):555-67
   PubMed Web of Science ®Google Scholar
• Farley J, Brady WE, Vathipadiekal V, et al. Selumetinib in women with recurrent low-grade serous carcinoma of the ovary or peritoneum: an open-label, single-arm, phase 2 study. Lancet Oncol 2013;14(2):134-40
   PubMed Web of Science ®Google Scholar
• Ho AL, Grewal RK, Leboeuf R, et al. Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. N Engl J Med 2013;368(7):623-32
   PubMed Web of Science ®Google Scholar
• Carvajal RD, Sosman JA, Quevedo F, et al. Phase II study of selumetinib (sel) versus temozolomide (TMZ) in gnaq/Gna11 (Gq/11) mutant (mut) uveal melanoma (UM). J Clin Oncol 2013;31(Suppl):abstract CRA9003
   Google Scholar
• Jain N, Curran E, Iyengar NM, et al. Phase II study of the oral MEK inhibitor selumetinib (AZD6244) in advanced acute myeloid leukemia (AML). J Clin Oncol 2012;30(Suppl):abstract 6582
   Google Scholar
• Jänne PA, Shaw AT, Pereira JR, et al. Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study. Lancet Oncol 2013;14(1):38-47
   PubMed Web of Science ®Google Scholar
• Robert C, Dummer R, Gutzmer R, et al. Selumetinib plus dacarbazine versus placebo plus dacarbazine as first-line treatment for BRAF-mutant metastatic melanoma: a phase 2 double-blind randomised study. Lancet Oncol 2013;14(8):733-40
   PubMed Web of Science ®Google Scholar
• Gupta A, Love S, Schuh A, et al. DOC-MEK: A double-blind randomized phase II trial of docetaxel with or without selumetinib (AZD6244; ARRY-142886) in wt BRAF advanced melanoma. J Clin Oncol 2013;31(Suppl):abstract 9068
   Google Scholar
• Hochster HS, Messersmith WA, O'Neil BH, et al. The MEK inhibitor selumetinib ([SEL], AZD6244, ARRY-142886) plus irinotecan (IRI) as second-line therapy for KRAS-mutated (KRASm) metastatic colorectal cancer (CRC). J Clin Oncol 2013;31(Suppl):abstract 3587
   Google Scholar
• Middleton MR, Dummer R, Gutzmer R, et al. Phase II double-blind, randomized study of selumetinib (SEL) plus dacarbazine (DTIC) versus placebo (PBO) plus DTIC as first-line treatment for advanced BRAF-mutant cutaneous or unknown primary melanoma. J Clin Oncol 2013;31(Suppl):abstract 9004
   Google Scholar
• Ko AH, Tempero MA, Bekaii-Saab TB, et al. Dual MEK/EGFR inhibition for advanced, chemotherapy-refractory pancreatic cancer: A multicenter phase II trial of selumetinib (AZD6244; ARRY-142886) plus erlotinib. J Clin Oncol 2013;31(Suppl):abstract 4014
   Google Scholar
• Carter CA, Rajan A, Szabo E, et al. Two parallel randomized phase II studies of selumetinib (S) and erlotinib (E) in advanced non-small cell lung cancer selected by KRAS mutations. J Clin Oncol 2013;31(Suppl):abstract 8026
   Google Scholar
• Deming DA, Schelman WR, Lubner SJ, et al. A phase I study of selumetinib (AZD6244/ARRY-142866) in combination with cetuximab (cet) in refractory solid tumors and KRAS mutant colorectal cancer (CRC). J Clin Oncol 2012;30(Suppl):abstract 3103
   Google Scholar
• Chung VM, McDonough S, Philip PA, et al. SWOG S1115: Randomized phase II clinical trial of selumetinib (AZD6244; ARRY 142886) hydrogen sulfate (NSC-748727) and MK-2206 (NSC-749607) versus mFOLFOX in patients withmetastatic pancreatic cancer after prior chemotherapy. J Clin Oncol 2013;31(Suppl):abstract TPS4145
   Google Scholar
• Speranza G, Kinders RJ, Khin S, et al. Pharmacodynamic biomarker-driven trial of MK-2206, an AKT inhibitor, with AZD6244 (selumetinib), a MEK inhibitor, in patients with advanced colorectal carcinoma (CRC). J Clin Oncol 2012;30(Suppl):abstract 3529
   Google Scholar
• Tolcher AW, Baird RD, Patnaik A, et al. A phase I dose-escalation study of oral MK-2206 (allosteric AKT inhibitor) with oral selumetinib (AZD6244; MEK inhibitor) in patients with advanced or metastatic solid tumors. J Clin Oncol 2011;29(Suppl):abstract 3004
   Google Scholar
• Kim K, Kong SY, Fulciniti M, 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. Br J Haematol 2010;149(4):537-49
   PubMed Web of Science ®Google Scholar
• Yoon J, Koo KH, Choi KY. MEK1/2 inhibitors AS703026 and AZD6244 may be potential therapies for KRAS mutated colorectal cancer that is resistant to EGFR monoclonal antibody therapy. Cancer Res 2011;71(2):445-53
   PubMed Web of Science ®Google Scholar
• Martinelli E, Troiani T, D'Aiuto E, et al. Antitumor activity of pimasertib, a selective MEK 1/2 inhibitor, in combination with PI3K/mTOR inhibitors or with multi-targeted kinase inhibitors in pimasertib-resistant human lung and colorectal cancer cells. Int J Cancer 2013;133(9):2089-101
   PubMed Web of Science ®Google Scholar
• Macarulla T, Tabernero J, Cervantes A, et al. Phase I/II study of FOLFIRI plus the MEK1/2 inhibitor pimasertib (MSC1936369b) as second-line treatment for kras mutated metastatic colorectal cancer. Ann Oncol 2012;23(Suppl 4):PD-0024
   Google Scholar
• Verslype C, Hammel P, Hidalgo M, et al. Pimasertib plus gemcitabine in metastatic pancreatic adenocarcinoma: Results of a safety run-in part of a phase II trial. J Clin Oncol 2013;31(Suppl):abstract 4041
   Google Scholar
• Heist RS, Gandhi L, Shapiro G, et al. Combination of a MEK inhibitor, pimasertib (MSC1936369B), and a PI3K/mTOR inhibitor, SAR245409, in patients with advanced solid tumors: Results of a phase Ib dose-escalation trial. J Clin Oncol 2013;31(Suppl):abstract 2530
   Google Scholar
• Iverson C, Larson G, Lai C, et al. RDEA119/BAY 869766: a potent, selective, allosteric inhibitor of MEK1/2 for the treatment of cancer. Cancer Res 2009;69(17):6839-47
   PubMed Web of Science ®Google Scholar
• Chang Q, Chapman MS, Miner JN, et al. Antitumour activity of a potent MEK inhibitor RDEA119/BAY 869766 combined with rapamycin in human orthotopic primary pancreatic cancer xenografts. BMC Cancer 2010;10:515
   PubMed Web of Science ®Google Scholar
• Liu D, Xing J, Trink B, Xing M. BRAF mutation-selective inhibition of thyroid cancer cells by the novel MEK inhibitor RDEA119 and genetic-potentiated synergism with the mTOR inhibitor temsirolimus. Int J Cancer 2010;127(12):2965-73
   PubMed Web of Science ®Google Scholar
• Diep CH, Munoz RM, Choudhary A, et al. Synergistic effect between erlotinib and MEK inhibitors in KRAS wild-type human pancreatic cancer cells. Clin Cancer Res 2011;17(9):2744-56
   PubMed Web of Science ®Google Scholar
• Gore L, Lewis K, Von Hoff DD, 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. J Clin Oncol 2011;29(Suppl):abstract 3007
   Google Scholar
• Van Laethem JL, Heinemann V, Martens UM, et al. A phase I/II study of the MEK inhibitor BAY 86-9766 (BAY) in combination with gemcitabine (GEM) in patients with nonresectable, locally advanced or metastatic pancreatic cancer (PC): Phase I dose-escalation results. J Clin Oncol 2012;30(Suppl):abstract 4050
   Google Scholar
• Lim HY, Yen C-J, Tak W-Y, 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). J Clin Oncol 2012;30(Suppl):abstract 4103
   Google Scholar
• Wong H, Vernillet L, Peterson A, et al. Bridging the gap between preclinical and clinical studies using pharmacokinetic-pharmacodynamic modeling: an analysis of GDC-0973, a MEK inhibitor. Clin Cancer Res 2012;18(11):3090-9
   PubMed Web of Science ®Google Scholar
• Hoeflich KP, Merchant M, Orr C, et al. Intermittent administration of MEK inhibitor GDC-0973 plus PI3K inhibitor GDC-0941 triggers robust apoptosis and tumor growth inhibition. Cancer Res 2012;72(1):210-19
   PubMed Web of Science ®Google Scholar
• Choo EF, Ng CM, Berry L, et al. PK-PD modeling of combination efficacy effect from administration of the MEK inhibitor GDC-0973 and PI3K inhibitor GDC-0941 in A2058 xenografts. Cancer Chemother Pharmacol 2013;71(1):133-43
   PubMed Web of Science ®Google Scholar
• Shapiro G, LoRusso P, Kwak EL, et al. Clinical combination of the MEK inhibitor GDC-0973 and the PI3K inhibitor GDC-0941: A first-in-human phase Ib study testing daily and intermittent dosing schedules in patients with advanced solid tumors. J Clin Oncol 2011;29(Suppl):abstract 3005^
   Google Scholar
• LoRusso P, Shapiro G, Pandya SS, 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. J Clin Oncol 2012;30(Suppl):abstract 2566
   Google Scholar
• McArthur G, Gonzalez R, Pavlick A, et al. Vemurafenib (VEM) and MEK inhibitor, cobimetinib (GDC-0973), in advanced BRAFV600-mutated melanoma (BRIM7): dose-escalation and expansion results of a phase IB study [abstract 3703]. ESMO/ECCO/ESTRO Meeting 2013
   Google Scholar
• Finn RS, Javle MM, Tan BR, et al. A phase I study of MEK inhibitor MEK162 (ARRY-438162) in patients with biliary tract cancer. J Clin Oncol 2012;30(Suppl 4):abstract 220
   Google Scholar
• Ascierto PA, Schadendorf D, Berking C, et al. MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study. Lancet Oncol 2013;14(3):249-56
   PubMed Web of Science ®Google Scholar
• Martinez-Garcia M, Banerji U, Albanell J, 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):4806-19
   PubMed Web of Science ®Google Scholar
• Honda K, Yamamoto N, Nokihara H, et al. Phase I and pharmacokinetic/pharmacodynamic study of RO5126766, a first-in-class dual Raf/MEK inhibitor, in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol 2013;72(3):577-84
   PubMed Web of Science ®Google Scholar
• Isshiki Y, Kohchi Y, Iikura H, et al. Design and synthesis of novel allosteric MEK inhibitor CH4987655 as an orally available anticancer agent. Bioorg Med Chem Lett 2011;21(6):1795-801
   PubMed Web of Science ®Google Scholar
• Leijen S, Middleton MR, Tresca P, 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. Clin Cancer Res 2012;18(17):4794-805
   PubMed Web of Science ®Google Scholar
• Cohen RB, Aamdal S, Nyakas M, et al. A phase I dose-finding, safety and tolerability study of AZD8330 in patients with advanced malignancies. Eur J Cancer 2013;49(7):1521-9
   PubMed Web of Science ®Google Scholar
• Henderson YC, Chen Y, Frederick MJ, et al. MEK inhibitor PD0325901 significantly reduces the growth of papillary thyroid carcinoma cells in vitro and in vivo. Mol Cancer Ther 2010;9(7):1968-76
   PubMed Web of Science ®Google Scholar
• Lorusso PM, Adjei AA, Varterasian M, et al. Phase I and pharmacodynamic study of the oral MEK inhibitor CI-1040 in patients with advanced malignancies. J Clin Oncol 2005;23(23):5281-93
   PubMed Web of Science ®Google Scholar
• Haura EB, Ricart AD, Larson TG, et al. A phase II study of PD-0325901, an oral MEK inhibitor, in previously treated patients with advanced non-small cell lung cancer. Clin Cancer Res 2010;16(8):2450-7
   PubMed Web of Science ®Google Scholar
• Heidorn SJ, Milagre C, Whittaker S, et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell 2010;140(2):209-21
   PubMed Web of Science ®Google Scholar
• Poulikakos PI, Zhang C, Bollag G, et al. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 2010;464(7287):427-30
   PubMed Web of Science ®Google Scholar
• Arnault JP, Mateus C, Escudier B, et al. Skin tumors induced by sorafenib; paradoxic RAS-RAF pathway activation and oncogenic mutations of HRAS, TP53, and TGFBR1. Clin Cancer Res 2012;18(1):263-72
   PubMed Web of Science ®Google Scholar
• Su F, Viros A, Milagre C, et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med 2012;366(3):207-15
   PubMed Web of Science ®Google Scholar
• Hatzivassiliou G, Haling JR, Chen H, et al. Mechanism of MEK inhibition determines efficacy in mutant KRAS-versus BRAF-driven cancers. Nature 2013;501(7466):232-6
   PubMed Web of Science ®Google Scholar
• Mirzoeva OK, Das D, Heiser LM, et al. Basal subtype and MAPK/ERK kinase (MEK)-phosphoinositide 3-kinase feedback signaling determine susceptibility of breast cancer cells to MEK inhibition. Cancer Res 2009;69(2):565-72
   PubMed Web of Science ®Google Scholar
• Shimizu T, Tolcher AW, Papadopoulos KP, et al. The clinical effect of the dual-targeting strategy involving PI3K/AKT/mTOR and RAS/MEK/ERK pathways in patients with advanced cancer. Clin Cancer Res 2012;18(8):2316-25
   PubMed Web of Science ®Google Scholar
• Tentori L, Lacal PM, Graziani G. Challenging resistance mechanisms to therapies for metastatic melanoma. Trends Pharmacol Sci 2013;34(12):656-66
   PubMed Web of Science ®Google Scholar
• Johannessen CM, Boehm JS, Kim SY, et al. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 2010;468(7326):968-72
   PubMed Web of Science ®Google Scholar
• Nazarian R, Shi H, Wang Q, et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 2010;468(7326):973-7
   PubMed Web of Science ®Google Scholar