MEK1 and MEK2 inhibitors and cancer therapy: The long and winding road

Nature Reviews Cancer

Volumn 15, Issue 10, 2015, Pages 577-592

  Caunt, Christopher J ^a   Sale, Matthew J ^b   Smith, Paul D ^c   Cook, Simon J ^b  

^a University of Bath   (United Kingdom)

^b BABRAHAM INSTITUTE   (United Kingdom)

^c IMPERIAL CANCER RESEARCH FUND   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

B RAF KINASE; DOCETAXEL; GEMCITABINE; IRINOTECAN; MITOGEN ACTIVATED PROTEIN KINASE KINASE 1; MITOGEN ACTIVATED PROTEIN KINASE KINASE 1 INHIBITOR; MITOGEN ACTIVATED PROTEIN KINASE KINASE 2; MITOGEN ACTIVATED PROTEIN KINASE KINASE 2 INHIBITOR; MONOCLONAL ANTIBODY; PIMASERTIB; PROTEIN TYROSINE KINASE INHIBITOR; RAF PROTEIN; UNCLASSIFIED DRUG; MAP2K1 PROTEIN, HUMAN; MAP2K2 PROTEIN, HUMAN; PROTEIN KINASE INHIBITOR;

CANCER COMBINATION CHEMOTHERAPY; CANCER RESISTANCE; CANCER THERAPY; COMPLEX FORMATION; DIARRHEA; DRUG DOSE REGIMEN; DRUG MECHANISM; DRUG TARGETING; EDEMA; ENZYME ACTIVATION; ENZYME PHOSPHORYLATION; ENZYME REACTIVATION; FATIGUE; GENE MUTATION; HEART DISEASE; HUMAN; MONOTHERAPY; NEGATIVE FEEDBACK; NUCLEAR REPROGRAMMING; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; PROTEIN FUNCTION; RANDOMIZED CONTROLLED TRIAL (TOPIC); RASH; REVIEW; SIDE EFFECT; ANTAGONISTS AND INHIBITORS; DRUG EFFECTS; METABOLISM; NEOPLASMS; PHYSIOLOGY; SIGNAL TRANSDUCTION;

HUMANS; MAP KINASE KINASE 1; MAP KINASE KINASE 2; MAP KINASE SIGNALING SYSTEM; NEOPLASMS; PROTEIN KINASE INHIBITORS; SIGNAL TRANSDUCTION;

EID: 84942307392     PISSN: 1474175X     EISSN: 14741768     Source Type: Journal    
DOI: 10.1038/nrc4000     Document Type: Review

References (198)

1. Yoon, S., & Seger, R. The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions. Growth Factors 24, 21-44 (2006
2. Karnoub, A. E., & Weinberg, R. A. Ras oncogenes: split personalities. Nat. Rev. Mol. Cell Biol. 9, 517-531 (2008
3. von Kriegsheim, A., et al. Cell fate decisions are specified by the dynamic ERK interactome. Nat. Cell Biol. 11, 1458-1464 (2009
4. Meloche, S., & Pouysségur, J. The ERK1/2 mitogen-Activated protein kinase pathway as a master regulator of the G1 to S phase transition. Oncogene 26, 3227-3239 (2007
5. Balmanno, K., & Cook, S. J. Tumour cell survival signalling by the ERK1/2 pathway. Cell Death Differ. 16, 368-377 (2009
6. Bromberg-White, J. L., Andersen, N. J., & Duesbery, N. S. MEK genomics in development and disease. Brief. Funct. Genom. 11, 300-310 (2012
7. Ying, Q. L., et al. The ground state of embryonic stem cell self-renewal. Nature 453, 519-523 (2008
8. Hanahan, D., & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57-70 (2000
9. Hanahan, D., & Weinberg, R A. Hallmarks of cancer: the next generation Cell 144, 646-674 (2011
10. Sebolt-Leopold, J. S., & Herrera, R. Targeting the mitogen-Activated protein kinase cascade to treat cancer. Nat. Rev. Cancer. 4, 937-947 (2004
11. Montagut, C., & Settleman, J. Targeting the RAF-MEK-ERK pathway in cancer therapy. Cancer Lett. 283, 125-134 (2009
12. Samatar, A. A., & Poulikakos, P. I. Targeting RAS-ERK signalling in cancer: promises and challenges. Nat. Rev. Drug Discov. 13, 928-942 (2014
13. Dudley, D. T., Pang, L., Decker, S. J., Bridges, A. J., & Saltiel, A. R. A synthetic inhibitor of the mitogen-Activated protein kinase cascade. Proc. Natl Acad. Sci. USA 92, 7686-7689 (1995
14. Sebolt-Leopold, J. S., et al. Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo. Nature Med. 5, 810-816 (1999
15. Frémin, C., & Meloche, S. From basic research to clinical development of MEK1/2 inhibitors for cancer therapy. J. Hematol. Oncol. 3, 8 (2010
16. Gilmartin, A. G., 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. 17, 989-1000 (2011
17. Davies, H., et al. Mutations of the BRAF gene in human cancer. Nature 417, 949-954 (2002
18. Bollag, G., et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature 467, 596-599 (2010
19. Bollag, G. Vemurafenib: the first drug approved for BRAF-mutant cancer. Nat. Rev. Drug Discov. 11, 873-886 (2012
20. Ascierto, P. A., et al. Phase II trial (BREAK 2) of the BRAF inhibitor dabrafenib (GSK2118436) in patients with metastatic melanoma. J. Clin. Oncol. 31, 3205-3211 (2013
21. Holderfield, M., Deuker, M. M., McCormick, F., & McMahon, M. Targeting RAF kinases for cancer therapy: BRAF-mutated melanoma and beyond. Nat. Rev. Cancer. 14, 455-467 (2014
22. Good, M. C., Zalatan, J. G., & Lim, W. A. Scaffold proteins: hubs for controlling the flow of cellular information. Science 332, 680-686 (2011
23. Ramos, J. W. The regulation of extracellular signal-regulated kinase (ERK) in mammalian cells. Int. J. Biochem. Cell Biol. 40, 2707-2719 (2008
24. Caunt, C. J., & Keyse, S. M. Dual-specificity MAP kinase phosphatases (MKPs): shaping the outcome of MAP kinase signalling. FEBS J. 280, 489-504 (2013
25. Zhang, Z., et al. Dual specificity phosphatase 6 (DUSP6) is an ETS-regulated negative feedback mediator of oncogenic ERK signaling in lung cancer cells. Carcinogenesis 31, 577-586 (2010
26. Rushworth, L. K., et al. Dual-specificity phosphatase 5 regulates nuclear ERK activity and suppresses skin cancer by inhibiting mutant Harvey-Ras (HRasQ61L)-driven SerpinB2 expression. Proc. Natl Acad. Sci. USA 111, 18267-18272 (2014
27. Moriceau, G., et al. Tunable-combinatorial mechanisms of acquired resistance limit the efficacy of BRAF/MEK cotargeting but result in melanoma drug addiction. Cancer Cell 27, 240-256 (2015
28. Duncan, J. S., et al. Dynamic reprogramming of the kinome in response to targeted MEK inhibition in triple-negative breast cancer. Cell 149, 307-321 (2012
29. Fawdar, S., et al. Targeted genetic dependency screen facilitates identification of actionable mutations in FGFR4, MAP3K9, and PAK5 in lung cancer. Proc. Natl Acad. Sci. USA 110, 12426-12431 (2013
30. Johannessen, C. M., et al. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 468, 968-972 (2010
31. Marusiak, A. A., et al. Mixed lineage kinases activate MEK independently of RAF to mediate resistance to RAF inhibitors. Nat. Commun. 5, 3901 (2014
32. Chiariello, M., Marinissen, M. J., & Gutkind, J. S. Multiple mitogen-Activated protein kinase signaling pathways connect the Cot oncoprotein to the c jun promoter and to cellular transformation. Mol. Cell. Biol. 20, 1747-1758 (2000
33. Todd, D. E., et al. ERK1/2 and p38 cooperate to induce a p21CIP1-dependent G1 cell cycle arrest. Oncogene 23, 3284-3295 (2004
34. Johnson, G. L., Dohlman, H. G., & Graves, L. M. MAPK kinase kinases (MKKKs) as a target class for small-molecule inhibition to modulate signaling networks and gene expression. Curr. Opin. Chem. Biol. 9, 325-331 (2005
35. Cuevas, B. D., Abell, A. N., & Johnson, G. L. Role of mitogen-Activated protein kinase kinase kinases in signal integration. Oncogene 26, 3159-3171 (2007
36. Roskoski, R. MEK1/2 dual-specificity protein kinases: structure and regulation. Biochem. Biophys. Res. Commun. 417, 5-10 (2012
37. Procaccia, S., & Seger, R. in Encyclopedia of Signaling Molecules (ed. Choi, S.) 1051-1058 (Springer, 2012
38. Zheng, C. F., & Guan, K. L. Activation of MEK family kinases requires phosphorylation of two conserved Ser/Thr residues. EMBO J. 13, 1123-1131 (1994
39. Alessi, D R. Identification of the sites in MAP kinase kinase 1 phosphorylated by p74raf 1. EMBO J. 13, 1610-1619 (1994
40. Eblen, S. T., Slack, J. K., Weber, M. J., & Catling, A. D. Rac-PAK signaling stimulates extracellular signal-regulated kinase (ERK) activation by regulating formation of MEK1-ERK complexes. Mol. Cell. Biol. 22, 6023-6033 (2002
41. Eblen, S. T., et al. Mitogen-Activated protein kinase feedback phosphorylation regulates MEK1 complex formation and activation during cellular adhesion. Mol. Cell. Biol. 24, 2308-2317 (2004
42. Catalanotti, F., et al. A Mek1-Mek2 heterodimer determines the strength and duration of the Erk signal. Nat. Struct. Mol. Biol. 16, 294-303 (2009
43. Bélanger, L. F., et al. Mek2 is dispensable for mouse growth and development. Mol. Cell. Biol. 23, 4778-4787 (2003
44. Giroux, S., et al. Embryonic death of Mek1 deficient mice reveals a role for this kinase in angiogenesis in the labyrinthine region of the placenta. Curr. Biol. 9, 369-372 (1999
45. Cowley, S., Paterson, H., Kemp, P., & Marshall, C. J. Activation of MAP kinase kinase is necessary and sufficient for PC12 differentiation and for transformation of NIH 3T3 cells. Cell 77, 841-852 (1994
46. Mansour, S. J., et al. Transformation of mammalian cells by constitutively active MAP kinase kinase. Science 265, 966-970 (1994
47. Solit, D. B., et al. BRAF mutation predicts sensitivity to MEK inhibition. Nature 439, 358-362 (2006
48. Dry, J. R. Transcriptional pathway signatures predict MEK addiction and response to selumetinib (AZD6244). Cancer Res. 70, 2264-2273 (2010
49. Joseph, E. W., et al. The RAF inhibitor PLX4032 inhibits ERK signaling and tumor cell proliferation in a V600E BRAF-selective manner. Proc. Natl Acad. Sci. USA 107, 14903-14908 (2010
50. Heidorn, S. J., et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell 140, 209-221 (2010
51. Poulikakos, P. I., Zhang, C., Bollag, G., Shokat, K. M., & Rosen, N. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-Type BRAF. Nature 464, 427-430 (2010
52. Hatzivassiliou, G., et al. RAF inhibitors prime wild-Type RAF to activate the MAPK pathway and enhance growth. Nature 464, 431-435 (2010
53. Holderfield, M., et al. RAF inhibitors activate the MAPK pathway by relieving inhibitory autophosphorylation. Cancer Cell 23, 594-602 (2013
54. Rodriguez-Viciana, P., et al. Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome. Science 311, 1287-1290 (2006
55. Bansal, A., Ramirez, R. D., & Minna, J. D. Mutation analysis of the coding sequences of MEK 1 and MEK 2 genes in human lung cancer cell lines. Oncogene 14, 1231-1234 (1997
56. Estep, A. L., Palmer, C. McCormick, F., & Rauen, K. A. Mutation analysis of BRAF, MEK1 and MEK2 in 15 ovarian cancer cell lines: implications for therapy. PLoS ONE 2, e1279 (2007
57. Marks, J. L., et al. Novel MEK1 mutation identified by mutational analysis of epidermal growth factor receptor signaling pathway genes in lung adenocarcinoma. Cancer Res. 68, 5524-5528 (2008
58. Murugan, A. K., Dong, J., Xie, J., & Xing, M. MEK1 mutations, but not ERK2 mutations, occur in melanomas and colon carcinomas, but none in thyroid carcinomas. Cell Cycle 8, 2122-2124 (2009
59. Nikolaev, S. I., et al. Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma. Nat. Genet. 44, 133-139 (2011
60. Arcila, M. E., et al. MAP2K1 (MEK1) mutations define a distinct subset of lung adenocarcinoma associated with smoking. Clin. Cancer Res. 21, 1935-1943 (2015
61. Blasco, R. B., et al. c Raf, but not B Raf, is essential for development of K Ras oncogene-driven non-small cell lung carcinoma. Cancer Cell. 19, 652-663 (2011
62. Karreth, FA., Frese, K. K., DeNicola, G. M., Baccarini, M., & Tuveson, D. A. C Raf is required for the initiation of lung cancer by K RasG12D. Cancer Discov. 1, 128-136 (2011
63. Alessi, D. R., Cuenda, A., Cohen, P., Dudley, D. T., & Saltiel, A. R. PD 098059 is a specific inhibitor of the activation of mitogen-Activated protein kinase kinase in vitro and in vivo. J. Biol. Chem. 270, 27489-27494 (1995
64. Favata, M. F., et al. Identification of a novel inhibitor of mitogen-Activated protein kinase kinase. J. Biol. Chem. 273, 18623-18632 (1998
65. Mody, N., Leitch, J., Armstrong, C., Dixon, J., & Cohen, P. Effects of MAP kinase cascade inhibitors on the MKK5/ERK5 pathway. FEBS Lett. 502, 21-24 (2001
66. Squires, M. S., Nixon, P. M., & Cook, S. J. Cell-cycle arrest by PD184352 requires inhibition of extracellular signal-regulated kinases (ERK) 1/2 but not ERK5/BMK1. Biochem. J. 366, 673-680 (2002
67. Ohren, J. F., et al. Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition. Nat. Struct. Mol. Biol. 11, 1192-1197 (2004
68. Yeh, T. C., et al. Biological characterization of ARRY 142886 (AZD6244), a potent, highly selective mitogen-Activated protein kinase kinase 1/2 inhibitor. Clin. Cancer Res. 13, 1576-1583 (2007
69. Fischmann, T. O., et al. Crystal structures of MEK1 binary and ternary complexes with nucleotides and inhibitors. Biochemistry 48, 2661-2674 (2009
70. Rinehart, J., et al. Multicenter phase II study of the oral MEK inhibitor, CI 1040, in patients with advanced non-small-cell lung, breast, colon, and pancreatic cancer. J. Clin. Oncol. 22, 4456-4462 (2004
71. Smith, C. K., & Windsor, W. T. Thermodynamics of nucleotide and non-ATP-competitive inhibitor binding to MEK1 by circular dichroism and isothermal titration calorimetry. Biochemistry 46, 1358-1367 (2007
72. Delaney, A. M., Printen, J. A., Chen, H., Fauman, E. B., & Dudley, D. T. Identification of a novel mitogen-Activated protein kinase kinase activation domain recognized by the inhibitor PD 184352. Mol. Cell. Biol. 22, 7593-7602 (2002
73. Friday, B. B., et al. BRAF V600E disrupts AZD6244 induced abrogation of negative feedback pathways between extracellular signal-regulated kinase and Raf proteins. Cancer Res. 68, 6145-6153 (2008
74. Hatzivassiliou, G., et al. Mechanism of MEK inhibition determines efficacy in mutant KRAS-versus BRAF-driven cancers. Nature 501, 232-236 (2013
75. Lito, P., et al. Disruption of CRAF-mediated MEK activation is required for effective MEK inhibition in KRAS mutant tumors. Cancer Cell 25, 697-710 (2014
76. Pratilas, C. A., et al. V600EBRAF is associated with disabled feedback inhibition of RAF-MEK signaling and elevated transcriptional output of the pathway. Proc. Natl Acad. Sci. USA 106, 4519-4524 (2009
77. Lito, P., et al. Relief of profound feedback inhibition of mitogenic signaling by RAF inhibitors attenuates their activity in BRAFV600E melanomas. Cancer Cell 22, 668-682 (2012
78. Ishii, N., et al. Enhanced inhibition of ERK signaling by a novel allosteric MEK inhibitor, CH5126766, that suppresses feedback reactivation of RAF activity. Cancer Res. 73, 4050-4060 (2013
79. Isshiki, Y., et al. Design and synthesis of novel allosteric MEK inhibitor CH4987655 as an orally available anticancer agent. Bioorg. Med. Chem. Lett. 21, 1795-1801 (2011
80. Dickson, M. A. Molecular pathways: CDK4 inhibitors for cancer therapy. Clin. Cancer Res. 20, 3379-3383 (2014
81. Smalley, K. S., et al. Increased cyclin D1 expression can mediate BRAF inhibitor resistance in BRAF V600E mutated melanomas. Mol. Cancer Ther. 7, 2876-2883 (2008
82. Aguirre, A. J., et al. Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. Genes Dev. 17, 3112-3126 (2003
83. Carragher, L. A., et al. V600EBraf induces gastrointestinal crypt senescence and promotes tumour progression through enhanced CpG methylation of p16INK4a. EMBO Mol. Med. 2, 458-471 (2010
84. Robinson, J. P., et al. Activated MEK cooperates with Ink4a/Arf loss or Akt activation to induce gliomas in vivo. Oncogene 30, 1341-1350 (2011
85. Franco, J., Witkiewicz, A. K., & Knudsen, E. S. CDK4/6 inhibitors have potent activity in combination with pathway selective therapeutic agents in models of pancreatic cancer. Oncotarget 5, 6512-6525 (2014
86. Kwong, L. N., et al. Oncogenic NRAS signaling differentially regulates survival and proliferation in melanoma. Nat. Med. 18, 1503-1510 (2012
87. Balmanno, K., Chell, S. D., Gillings, A. S., Hayat, S., & Cook, S. J. 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. Int. J. Cancer. 125, 2332-2341 (2009
88. Halilovic, E., et al. PIK3CA mutation uncouples tumor growth and cyclin D1 regulation from MEK/ERK and mutant KRAS signaling. Cancer Res. 70, 6804-6814 (2010
89. Holt, S. V., et al. Enhanced apoptosis and tumor growth suppression elicited by combination of MEK (selumetinib) and mTOR kinase inhibitors (AZD8055). Cancer Res. 72, 1804-1813 (2012
90. Roberts, P. J., et al. Combined PI3K/mTOR and MEK inhibition provides broad antitumor activity in faithful murine cancer models. Clin. Cancer Res. 18, 5290-5303 (2012
91. Tolcher, A. W., et al. Antitumor activity in RAS-driven tumors by blocking AKT and MEK. Clin. Cancer Res. 21, 739-748 (2015
92. Dai, B., et al STAT3 mediates resistance to MEK inhibitor through microRNA miR 17. Cancer Res. 71, 3658-3668 (2011
93. Bid, H. K., et al. Development, characterization, and reversal of acquired resistance to the MEK1 inhibitor selumetinib (AZD6244) in an in vivo model of childhood astrocytoma. Clin. Cancer Res. 19, 6716-6729 (2013
94. Lin, L., et al. The Hippo effector YAP promotes resistance to RAF-And MEK-Targeted cancer therapies. Nat. Genet. 47, 250-256 (2015
95. Flaherty, K. T., et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N. Engl. J. Med. 367, 107-114 (2012
96. Turke, A. B., et al. MEK inhibition leads to PI3K/AKT activation by relieving a negative feedback on ERBB receptors. Cancer Res. 72, 3228-3237 (2012
97. Mirzoeva, O. K., et al. Subtype-specific MEK PI3kinase feedback as a therapeutic target in pancreatic adenocarcinoma. Mol. Cancer Ther. 12, 2213-2225 (2013
98. Montero-Conde, C., et al. Relief of feedback inhibition of HER3 transcription by RAF and MEK inhibitors attenuates their antitumor effects in BRAF-mutant thyroid carcinomas. Cancer Discov. 3, 520-533 (2013
99. Lee, H. J., et al. Drug resistance via feedback activation of Stat3 in oncogene-Addicted cancer cells. Cancer Cell 26, 207-221 (2014
100. Fiskus, W., et al. BET protein antagonist JQ1 is synergistically lethal with FLT3 tyrosine kinase inhibitor (TKI) and overcomes resistance to FLT3 TKI in AML cells expressing FLT-ITD. Mol. Cancer Ther. 13, 2315-2327 (2014
101. Little, A. S., Smith, P. D., & Cook, S. J. Mechanisms of acquired resistance to ERK1/2 pathway inhibitors. Oncogene 32, 1207-1215 (2013
102. Emery, C. M., et al. MEK1 mutations confer resistance to MEK and B RAF inhibition. Proc. Natl Acad. Sci. USA 106, 20411-20416 (2009
103. Hatzivassiliou, G., et al. ERK inhibition overcomes acquired resistance to MEK inhibitors. Mol. Cancer Ther. 11, 1143-1154 (2012
104. Morris, E. J., et al. Discovery of a novel ERK inhibitor with activity in models of acquired resistance to BRAF and MEK inhibitors. Cancer Discov. 3, 742-750 (2013
105. Villanueva, J., et al. Concurrent MEK2 mutation and BRAF amplification confer resistance to BRAF and MEK inhibitors in melanoma. Cell Rep. 4, 1090-1099 (2013
106. Corcoran, R. B., et al. BRAF gene amplification can promote acquired resistance to MEK inhibitors in cancer cells harboring the BRAF V600E mutation. Sci. Signal 3, ra84 (2010
107. Little, A. S., et al. Amplification of the driving oncogene, KRAS or BRAF, underpins acquired resistance to MEK1/2 inhibitors in colorectal cancer cells. Sci. Signal 4, ra17 (2011
108. Flaherty, K. T., et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N. Engl. J. Med. 367, 1694-1703 (2012
109. Infante, J. R., et al. Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial. Lancet Oncol. 13, 773-781 (2012
110. Musib, L., et al. Clinical pharmacokinetics of GDC 0973, an oral MEK inhibitor, in cancer patients: data from a Phase 1 study. Cancer Res. 71, 1304 (2011
111. Ribas, A., et al. Combination of vemurafenib and cobimetinib in patients with advanced BRAFV600-mutated melanoma: a Phase 1b study. Lancet Oncol. 15, 954-965 (2014
112. Adjei, A. A., 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. 26, 2139-2146 (2008
113. Houédé, N., et al. 600 pharmacokinetics and pharmacodynamics of a selective oral MEK1/2 inhibitor, pimasertib (MSC1936369B/AS703026), in patients with advanced solid tumors. Eur. J. Cancer 48, S184 (2012
114. Weekes, C. D., et al. Multicenter Phase I trial of the mitogen-Activated protein kinase 1/2 inhibitor BAY 86-9766 in patients with advanced cancer. Clin. Cancer Res. 19, 1232-1243 (2013
115. Kim, K. B., 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. 31, 482-489 (2013
116. Long, G. V., et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N. Engl. J. Med. 371, 1877-1888 (2014
117. Robert, C., et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N. Engl. J. Med. 372, 30-39 (2015
118. Zimmer, L., et al. Phase I expansion and pharmacodynamic study of the oral MEK inhibitor RO4987655 (CH4987655) in selected patients with advanced cancer with RAS-RAF mutations. Clin. Cancer Res. 20, 4251-4261 (2014
119. Bennouna, J., 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 29, 1021-1028 (2011
120. Ascierto, P. A., et al. MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label Phase 2 study. Lancet Oncol. 14, 249-256 (2013
121. Farley, J., 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. 14, 134-140 (2013
122. Bodocky, G., 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 30, 1216-1223 (2012
123. Bekaii-Saab, T., et al. Multi-institutional Phase II study of selumetinib in patients with metastatic biliary cancers. J. Clin. Oncol. 29, 2357-2363 (2011
124. Hainsworth, J. D., 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. 5, 1630-1636 (2010
125. Carvajal, R. D., et al. Effect of selumetinib versus chemotherapy on progression-free survival in uveal melanoma: a randomized clinical trial. JAMA 311, 2397-2405 (2014
126. Borthakur, G., et al. Phase I/II trial of the MEK1/2 inhibitor GSK1120212 (GSK212) in patients (pts) with relapsed/refractory myeloid malignancies: evidence of activity in pts with RAS mutation. J. Clin. Oncol. 29, 4251-4261 (2011
127. Jain, N., et al. Phase II study of the oral MEK inhibitor selumetinib in advanced acute myelogenous leukemia: a University of Chicago Phase II consortium trial. Clin. Cancer Res. 20, 490-498 (2014
128. Blumenschein, G. Jr et al. A randomized Phase 2 study of the MEK1/MEK2 inhibitor trametinib (GSK1120212) compared with docetaxel in KRAS-mutant advanced non-small cell lung cancer (NSCLC). Ann Oncol. 26, 894-901 (2015
129. Widemann, B. C., et al. Phase I study of the MEK1/2 inhibitor selumetinib (AZD6244) hydrogen sulfate in children and young adults with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PNs). J. Clin. Oncol. 32, S10018 (2014
130. Banerjee, A., et al. A phase 1 study of AZD6244 in children with recurrent or refractory low-grade gliomas: A Pediatric Brain Tumor Consortium report. J. Clin. Oncol. 32, 10065 (2014
131. Jones, D. T. W., et al. Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma Nat. Genet. 45, 927-932 (2013
132. Corcoran, R. B., et al. Phase 1-2 trial of the BRAF inhibitor dabrafenib (D) plus MEK inhibitor trametinib (T) in BRAF V600 mutant colorectal cancer (CRC): updated efficacy and biomarker analysis. J. Clin. Oncol. 32, S3517 (2014
133. Bendell, J. C., et al. Efficacy and tolerability in an open-label phase I/II study of MEK inhibitor trametinib (T), BRAF inhibitor dabrafenib (D), and anti-EGFR antibody panitumumab (P) in combination in patients (pts) with BRAF V600E mutated colorectal cancer (CRC). J. Clin. Oncol. 32, S3515 (2014
134. Chen, Z., et al. A murine lung cancer co clinical trial identifies genetic modifiers of therapeutic response. Nature 483, 613-617 (2012
135. Holt, S. V., et al. The MEK1/2 inhibitor, selumetinib (AZD6244; ARRY 142886), enhances anti-Tumour efficacy when combined with conventional chemotherapeutic agents in human tumour xenograft models. Br. J. Cancer 106, 858-866 (2012
136. Jänne, P. A., et al. Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, Phase 2 study. Lancet Oncol. 14, 38-47 (2013
137. Gandara, D. R., 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. 31, S8028 (2013
138. Infante, J. R., et al. A randomised, double-blind, placebo-controlled trial of trametinib, an oral MEK inhibitor, in combination with gemcitabine for patients with untreated metastatic adenocarcinoma of the pancreas. Eur. J. Cancer. 50, 2072-2081 (2014
139. Van Cutsem, E., et al. Phase II randomized trial of MEK inhibitor pimasertib or placebo combined with gemcitabine in the first-line treatment of metastatic pancreatic cancer. J. Clin. Oncol. 33, S344 (2015
140. Hochster, H. S., et al. Phase II study of selumetinib (AZD6244, ARRY 142886) plus irinotecan as second-line therapy in patients with K RAS mutated colorectal cancer. Cancer Chemother. Pharmacol. 75, 17-23 (2015
141. Bedard, P. L., et al. A Phase Ib dose-escalation study of the oral pan PI3K inhibitor buparlisib (BKM120) in combination with the oral MEK1/2 inhibitor trametinib (GSK1120212) in patients with selected advanced solid tumors. Clin. Cancer Res. 21, 730-738 (2015
142. Juric, D., et al. A phase 1b dose-escalation study of BYL719 plus binimetinib (MEK162) in patients with selected advanced solid tumors. J. Clin. Oncol. 32, S9051 (2014
143. Chakravarty, D., et al. Small-molecule MAPK inhibitors restore radioiodine incorporation in mouse thyroid cancers with conditional BRAF activation. J. Clin. Invest. 121, 4700-4711 (2011
144. Ho, A. L., et al. Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. N. Engl. J. Med. 368, 623-632 (2013
145. Falchook, G. S., et al. Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a Phase 1 dose-escalation trial. Lancet Oncol. 13, 782-789 (2012
146. Hauschild, A., et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, Phase 3 randomised controlled trial. Lancet 380, 358-365 (2012
147. Chapman, P. B., et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N. Engl. J. Med. 364, 2507-2516 (2011
148. Zhao, Y., & Adjei, A. A. The clinical development of MEK inhibitors. Nat. Rev. Clin. Oncol. 11, 385-400 (2014
149. Duncan, K. E., Chang, L. Y., & Patronas, M. MEK inhibitors: a new class of chemotherapeutic agents with ocular toxicity. Eye 29, 1003-1012 (2015
150. Robert, C., 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. 14, 733-740 (2013
151. LoRusso, P., 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. 30, S2566 (2012
152. Kurzrock, R., et al. Phase I dose-escalation of the oral MEK1/2 inhibitor GSK1120212 (GSK212) dosed in combination with the oral AKT inhibitor GSK2141795 (GSK795). J. Clin. Oncol. 29, S3085 (2011
153. Becerra, C., 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. 30, S3023 (2012
154. Pratilas, C. A., et al. Genetic predictors of MEK dependence in non-small cell lung cancer. Cancer Res. 68, 9375-9383 (2008
155. Jing, J., et al. Comprehensive predictive biomarker analysis for MEK inhibitor GSK1120212. Mol. Cancer Ther. 11, 720-729 (2012
156. Kelly, K., 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. 31, S8027 (2013
157. Abdel-Wahab, O., et al. Efficacy of intermittent combined RAF and MEK inhibition in a patient with concurrent BRAF-And NRAS-mutant malignancies. Cancer Discov. 4, 538-545 (2014
158. Loboda, A., et al. A gene expression signature of RAS pathway dependence predicts response to PI3K and RAS pathway inhibitors and expands the population of RAS pathway activated tumors. BMC Med. Genom. 3, 26 (2010
159. Lamba, S., et al. RAF suppression synergizes with MEK inhibition in KRAS mutant cancer cells. Cell Rep. 8, 1475-1483 (2014
160. Goetz, E. M. Ghandi, M., Treacy, D. J., Wagle, N., & Garraway, L. A. ERK mutations confer resistance to mitogen-Activated protein kinase pathway inhibitors. Cancer Res. 74, 7079-7089 (2014
161. Xing, F., et al. Concurrent loss of the PTEN and RB1 tumour suppressors attenuates RAF dependence in melanomas harboring V600EBRAF. Oncogene 31, 446-457 (2012
162. Sosman, J. A., et al. A Phase 1b/2 study of LEE011 in combination with binimetinib in patients with NRAS-mutant melanoma: early encouraging clinical activity. J. Clin. Oncol. 32, S9009 (2014
163. Sale, M. J., & Cook, S. J. The BH3 mimetic ABT 263 synergizes with the MEK1/2 inhibitor selumetinib/AZD6244 to promote BIM-dependent tumour cell death and inhibit acquired resistance. Biochem. J. 450, 285-294 (2013
164. Corcoran, R. B., et al. Synthetic lethal interaction of combined BCL XL and MEK inhibition promotes tumor regressions in KRAS mutant cancer models. Cancer Cell 23, 121-128 (2013
165. Liu, L., et al. The BRAF and MEK inhibitors dabrafenib and trametinib: effects on immune function and in combination with immunomodulatory antibodies targeting PD1, PD L1 and CTLA 4. Clin. Cancer Res. 21, 1639-1651 (2015
166. Sturm, O. E., et al. The mammalian MAPK/ERK pathway exhibits properties of a negative feedback amplifier. Sci. Signal 3, ra90 (2010
167. Heinrich, R., Neel, B. G., & Rapoport, T. A. Mathematical models of protein kinase signal transduction. Mol. Cell 9, 957-970 (2002
168. Voliotis, M., Perrett, R. M., McWilliams, C. McArdle, C. A., & Bowsher, C. G. Information transfer by leaky, heterogeneous, protein kinase signaling systems. Proc. Natl Acad. Sci. USA 111, E326-E333 (2014
169. Ebisuya, M., Kondoh, K., & Nishida, E. The duration, magnitude and compartmentalization of ERK MAP kinase activity: mechanisms for providing signaling specificity. J. Cell Sci. 118, 2997-3002 (2005
170. Kholodenko, B. N., Hancock, J. F., & Kolch, W. Signalling ballet in space and time. Nat. Rev. Mol. Cell Biol. 11, 414-426 (2010
171. Rajakulendran, T., Sahmi, M., Lefrançois, M., Sicheri, F., & Therrien, M. A dimerization-dependent mechanism drives RAF catalytic activation. Nature 461, 542-545 (2009
172. Rushworth, L. K., Hindley, A. D., O'Neill, E., & Kolch, W. Regulation and role of Raf 1/B Raf heterodimerization Mol. Cell. Biol. 26, 2262-2272 (2006
173. Dougherty, M. K., et al. Regulation of Raf 1 by direct feedback phosphorylation. Mol. Cell. 17, 215-224 (2005
174. Ritt, D. A., Monson, D. M., Specht, S. I., & Morrison, D. K. Impact of feedback phosphorylation and Raf heterodimerization on normal and mutant B Raf signaling. Mol. Cell. Biol. 30, 806-819 (2010
175. Fritsche-Guenther, R., et al. Strong negative feedback from Erk to Raf confers robustness to MAPK signalling. Mol. Syst. Biol. 7, 489 (2011
176. McKay, M. M., & Morrison, D. K. Integrating signals from RTKs to ERK/MAPK. Oncogene 26, 3113-3121 (2007
177. Yarden, Y., & Slikowski, M. X. Untangling the ErbB signalling network. Nat. Revs Mol. Cell. Biol. 2, 127-137 (2001
178. Chen, J., Fujii, K., Zhang, L., Roberts, T., & Fu, H. Raf 1 promotes cell survival by antagonizing apoptosis signal-regulating kinase 1 through a MEK-ERK independent mechanism. Proc. Natl Acad. Sci. USA 98, 7783-7788 (2001
179. Mielgo, A., et al. A MEK-independent role for CRAF in mitosis and tumor progression. Nat. Med. 17, 1641-1645 (2011
180. Lorusso, P. M., et al. Phase I and pharmacodynamic study of the oral MEK inhibitor CI 1040 in patients with advanced malignancies. J. Clin. Oncol. 23, 5281-5293 (2005
181. LoRusso, P. M., et al. Phase I pharmacokinetic and pharmacodynamic study of the oral MAPK/ERK kinase inhibitor PD 0325901 in patients with advanced cancers. Clin. Cancer Res. 16, 1924-1937 (2010
182. Lee, P. A., et al. Preclinical development of ARRY 162, a potent and selective MEK 1/2 inhibitor. Cancer Res. 70, S2515 (2010
183. Chen, X., et al. Combined PKC and MEK inhibition in uveal melanoma with GNAQ and GNA11 mutations. Oncogene 33, 4724-4734 (2014
184. Finn, R. S., et al. A Phase I study of MEK inhibitor MEK162 (ARRY 438162) in patients with biliary tract cancer. J. Clin. Oncol. 30, S220 (2012
185. Carter, L., et al. ARRY 162, a novel MEK inhibitor: results of a 14 day Phase 1a study in healthy subjects and a 28 day Phase 1b study in rheumatoid arthritis patients. American College of Rheumatology [online], https://acr.confex.com/acr/2008/webprogram/Paper3095.html (2008
186. Banerji, U., et al. The first in human study of the hydrogen sulfate (Hyd-sulfate) capsule of the MEK1/2 inhibitor AZD6244 (ARRY 142886): a Phase I open-label multicenter trial in patients with advanced cancer. Clin. Cancer Res. 16, 1613-1623 (2010)
187. Iverson, C., et al. RDEA119/BAY 869766: a potent, selective, allosteric inhibitor of MEK1/2 for the treatment of cancer. Cancer Res. 69, 6839-6847 (2009
188. Schmieder, R., et al. Allosteric MEK1/2 inhibitor refametinib (BAY 86-9766) in combination with sorafenib exhibits antitumor activity in preclinical murine and rat models of hepatocellular carcinoma. Neoplasia 15, 1161-1171 (2013
189. Lee, L., et al. The safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of CH4987655 in healthy volunteers: target suppression using a biomarker. Clin. Cancer Res. 15, 7368-7374 (2009
190. Leijen, S., 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. 18, 4794-4805 (2012
191. Kim, K., 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. 149, 537-549 (2010
192. Dong, Q., et al. Discovery of TAK 733, a potent and selective MEK allosteric site inhibitor for the treatment of cancer. Bioorg. Med. Chem. Lett. 21, 1315-1319 (2011
193. Nakamura, A., et al. Antitumor activity of the selective pan-RAF inhibitor TAK 632 in BRAF inhibitor-resistant melanoma. Cancer Res. 73, 7043-7055 (2013
194. Adjei, A. A., et al. Multicenter dose-escalation study of the investigational drug TAK 733, an oral MEK inhibitor in patients with advanced solid tumors; preliminary phase 1 result. Oncology PRO [online], http://oncologypro.esmo.org/Meeting-Resources/ESMO-2012/Multicenter-dose-escalation-study-of-The-investigational-drug-TAK-733-An-oral-MEK-inhibitor-in-patients-pts-with-Advanced-solid-Tumors-preliminary-phase-1-results (2012
195. Leonowens, C., et al. Concomitant oral and intravenous pharmacokinetics of trametinib, a MEK inhibitor, in subjects with solid tumours. Br. J. Clin. Pharmacol. 78, 524-532 (2014
196. Martinez-Garcia, M., 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. 18, 4806-4819 (2012
197. Hoeflich, K. P., et al. Intermittent administration of MEK inhibitor GDC 0973 plus PI3K inhibitor GDC 0941 triggers robust apoptosis and tumor growth inhibition. Cancer Res. 72, 210-219 (2012
198. El Khoueiry, A., et al. A first in human Phase I study to evaluate the MEK1/2 inhibitor GDC 0623 in patients with advanced solid tumors. Mol. Cancer Ther. 12, B75 (2013