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The clinical development of MEK inhibitors

Nature Reviews Clinical Oncology volume 11, pages 385–400 (2014)Cite this article

Subjects

Key Points

  • MEK1/2 have crucial roles in mediating cellular signals transduced from RAS–RAF, an oncogenic pathway implicated in numerous types of tumour, and are therefore attractive targets for cancer therapy

  • Although one MEK1/2 inhibitor, trametinib, has been approved by the FDA for the treatment of BRAF-mutant melanoma, the efficacy of MEK1/2 inhibitors in other tumours has been less encouraging

  • Promising therapeutic activity of certain MEK1/2 inhibitors has been demonstrated in NRAS-mutated melanoma and uveal melanoma, diseases in which RAF-targeted therapy has been ineffective

  • No predictive biomarkers of the outcomes of MEK1/2-inhibitor therapy have been identified to date, hindering the rational development of these compounds

  • Studies are evaluating combinations of MEK1/2 inhibitors and other targeted agents or cytotoxic chemotherapy aimed at mitigating resistance mechanisms and thus enhancing cancer therapy

Abstract

Aberrant activation of the RAS–RAF–MEK–ERK1/2 pathway occurs in more than 30% of human cancers. As part of this pathway, MEK1 and MEK2 have crucial roles in tumorigenesis, cell proliferation and inhibition of apoptosis and, therefore, MEK1/2 inhibition is an attractive therapeutic strategy in a number of cancers. Highly selective and potent non-ATP-competitive allosteric MEK1/2 inhibitors have been developed and assessed in numerous clinical studies over the past decade. These agents are not efficacious in a broad range of unselected cancers, although single-agent antitumour activity has been detected mainly in tumours that harbour mutations in genes encoding the members of the RAS and RAF protein families, such as certain melanomas. Combinations of MEK1/2 inhibitors and cytotoxic chemotherapy, and/or other targeted agents are being studied to expand the efficacy of this class of agents. Identifying predictive biomarkers, and delineating de novo and acquired resistance mechanisms are essential for the future clinical development of MEK inhibitors. We discuss the clinical experience with MEK inhibitors to date, and consider the novel approaches to MEK-inhibitor therapy that might improve outcomes and lead to the wider use of such treatments.

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Figure 1: Simplified schematic of MAPK signalling.
Figure 2: Abrogation of negative feedback pathways between ERK and RAF.

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References

  1. Robinson, M. J. & Cobb, M. H. Mitogen-activated protein kinase pathways. Curr. Opin. Cell Biol. 9, 180–186 (1997).

    Article  CAS  PubMed  Google Scholar 

  2. Chang, L. & Karin, M. Mammalian MAP kinase signalling cascades. Nature 410, 37–40 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. 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).

    Article  CAS  PubMed  Google Scholar 

  4. Pandey, S. K., Theberge, J. F., Bernier, M. & Srivastava, A. K. Phosphatidylinositol 3-kinase requirement in activation of the Ras/C-raf-1/MEK/ERK and p70(S6K) signaling cascade by the insulinomimetic agent vanadyl sulfate. Biochemistry 38, 14667–14675 (1999).

    Article  CAS  PubMed  Google Scholar 

  5. Marais, R. et al. Requirement of Ras-GTP–Raf complexes for activation of Raf-1 by protein kinase C. Science 280, 109–112 (1998).

    Article  CAS  PubMed  Google Scholar 

  6. Leevers, S. J., Paterson, H. F. & Marshall, C. J. Requirement for Ras in Raf activation is overcome by targeting Raf to the plasma membrane. Nature 369, 411–414 (1994).

    Article  CAS  PubMed  Google Scholar 

  7. Marais, R., Light, Y., Paterson, H. F. & Marshall, C. J. Ras recruits Raf-1 to the plasma membrane for activation by tyrosine phosphorylation. EMBO J. 14, 3136–3145 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kolch, W., Heidecker, G., Lloyd, P. & Rapp, U. R. Raf-1 protein kinase is required for growth of induced NIH/3T3 cells. Nature 349, 426–428 (1991).

    Article  CAS  PubMed  Google Scholar 

  9. Fischmann, T. O. et al. Crystal structures of MEK1 binary and ternary complexes with nucleotides and inhibitors. Biochemistry 48, 2661–2674 (2009).

    Article  CAS  PubMed  Google Scholar 

  10. Liang, H., Liu, T., Chen, F., Liu, Z. & Liu, S. A full-length 3D structure for MAPK/ERK kinase 2 (MEK2). Sci. China Life Sci. 54, 336–341 (2011).

    Article  CAS  PubMed  Google Scholar 

  11. 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).

    Article  CAS  PubMed  Google Scholar 

  12. Trujillo, J. I. MEK inhibitors: a patent review 2008–2010. Expert Opin. Ther. Pat. 21, 1045–1069 (2011).

    Article  CAS  PubMed  Google Scholar 

  13. Prior, I. A., Lewis, P. D. & Mattos, C. A comprehensive survey of Ras mutations in cancer. Cancer Res. 72, 2457–2467 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Xing, M. The T1799A BRAF mutation is not a germline mutation in familial nonmedullary thyroid cancer. Clin. Endocrinol. (Oxford) 63, 263–266 (2005).

    Article  CAS  Google Scholar 

  15. Sieben, N. L. et al. In ovarian neoplasms, BRAF, but not KRAS, mutations are restricted to low-grade serous tumours. J. Pathol. 202, 336–340 (2004).

    Article  CAS  PubMed  Google Scholar 

  16. Brose, M. S. et al. BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res. 62, 6997–7000 (2002).

    CAS  PubMed  Google Scholar 

  17. Friday, B. B. & Adjei, A. A. Advances in targeting the Ras/Raf/MEK/Erk mitogen-activated protein kinase cascade with MEK inhibitors for cancer therapy. Clin. Cancer Res. 14, 342–346 (2008).

    Article  CAS  PubMed  Google Scholar 

  18. COSMIC catalogue of somatic mutations in cancer. COSMIC gene overview: BRAF [online], (2014).

  19. Daub, H., Weiss, F. U., Wallasch, C. & Ullrich, A. Role of transactivation of the EGF receptor in signalling by G-protein-coupled receptors. Nature 379, 557–560 (1996).

    Article  CAS  PubMed  Google Scholar 

  20. Hou, P., Liu, D. & Xing, M. Genome-wide alterations in gene methylation by the BRAF V600E mutation in papillary thyroid cancer cells. Endocr. Relat. Cancer 18, 687–697 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Roskoski, R. Jr. ERK1/2 MAP kinases: structure, function, and regulation. Pharmacol. Res. 66, 105–143 (2012).

    Article  CAS  PubMed  Google Scholar 

  22. Meloche, S. & Pouyssegur, 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).

    Article  CAS  PubMed  Google Scholar 

  23. Shaul, Y. D. & Seger, R. The MEK/ERK cascade: from signaling specificity to diverse functions. Biochim. Biophys. Acta 1773, 1213–1226 (2007).

    Article  CAS  PubMed  Google Scholar 

  24. Lewis, T. S., Shapiro, P. S. & Ahn, N. G. Signal transduction through MAP kinase cascades. Adv. Cancer Res. 74, 49–139 (1998).

    Article  CAS  PubMed  Google Scholar 

  25. Alberola-Ila, J., Forbush, K. A., Seger, R., Krebs, E. G. & Perlmutter, R. M. Selective requirement for MAP kinase activation in thymocyte differentiation. Nature 373, 620–623 (1995).

    Article  CAS  PubMed  Google Scholar 

  26. Johnson, G. L. & Vaillancourt, R. R. Sequential protein kinase reactions controlling cell growth and differentiation. Curr. Opin. Cell Biol. 6, 230–238 (1994).

    Article  CAS  PubMed  Google Scholar 

  27. D'Angelo, G., Struman, I., Martial, J. & Weiner, R. I. Activation of mitogen-activated protein kinases by vascular endothelial growth factor and basic fibroblast growth factor in capillary endothelial cells is inhibited by the antiangiogenic factor 16-kDa N-terminal fragment of prolactin. Proc. Natl Acad. Sci. USA 92, 6374–6378 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Na, J., Furue, M. K. & Andrews, P. W. Inhibition of ERK1/2 prevents neural and mesendodermal differentiation and promotes human embryonic stem cell self-renewal. Stem Cell Res. 5, 157–169 (2010).

    Article  CAS  PubMed  Google Scholar 

  29. Raman, M., Chen, W. & Cobb, M. H. Differential regulation and properties of MAPKs. Oncogene 26, 3100–3112 (2007).

    Article  CAS  PubMed  Google Scholar 

  30. Repasky, G. A., Chenette, E. J. & Der, C. J. Renewing the conspiracy theory debate: does Raf function alone to mediate Ras oncogenesis? Trends Cell Biol. 14, 639–647 (2004).

    Article  CAS  PubMed  Google Scholar 

  31. Scita, G. et al. Signaling from Ras to Rac and beyond: not just a matter of GEFs. EMBO J. 19, 2393–2398 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Castellano, E. & Downward, J. RAS interaction with PI3K: more than just another effector pathway. Genes Cancer 2, 261–274 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Hamad, N. M. et al. Distinct requirements for Ras oncogenesis in human versus mouse cells. Genes Dev. 16, 2045–2057 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 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).

    Article  CAS  PubMed  Google Scholar 

  35. Flaherty, K. T. et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N. Engl. J. Med. 367, 107–114 (2012).

    Article  CAS  PubMed  Google Scholar 

  36. US Food and Drug Administration. NDA 204114 approval [online], (2013).

  37. Bollag, G. et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature 467, 596–599 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Wang, S., Ghosh, R. N. & Chellappan, S. P. Raf-1 physically interacts with Rb and regulates its function: a link between mitogenic signaling and cell cycle regulation. Mol. Cell Biol. 18, 7487–7498 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. O'Neill, E., Rushworth, L., Baccarini, M. & Kolch, W. Role of the kinase MST2 in suppression of apoptosis by the proto-oncogene product Raf-1. Science 306, 2267–2270 (2004).

    Article  CAS  PubMed  Google Scholar 

  41. Piazzolla, D., Meissl, K., Kucerova, L., Rubiolo, C. & Baccarini, M. Raf-1 sets the threshold of Fas sensitivity by modulating Rok-α signaling. J. Cell Biol. 171, 1013–1022 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Matallanas, D. et al. Raf family kinases: old dogs have learned new tricks. Genes Cancer 2, 232–260 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Rauch, J. et al. Heterogeneous nuclear ribonucleoprotein H blocks MST2-mediated apoptosis in cancer cells by regulating A-Raf transcription. Cancer Res. 70, 1679–1688 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Castellano, E. & Downward, J. Role of RAS in the regulation of PI 3-kinase. Curr. Top. Microbiol. Immunol. 346, 143–169 (2010).

    CAS  PubMed  Google Scholar 

  45. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. 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).

    Article  CAS  PubMed  Google Scholar 

  47. Brummer, T., Naegele, H., Reth, M. & Misawa, Y. Identification of novel ERK-mediated feedback phosphorylation sites at the C-terminus of B-Raf. Oncogene 22, 8823–8834 (2003).

    Article  CAS  PubMed  Google Scholar 

  48. Dougherty, M. K. et al. Regulation of Raf-1 by direct feedback phosphorylation. Mol. Cell 17, 215–224 (2005).

    Article  CAS  PubMed  Google Scholar 

  49. 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).

    Article  CAS  PubMed  Google Scholar 

  50. Flaherty, K. T. et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N. Engl. J. Med. 367, 1694–1703 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Ho, A. L. et al. Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. N. Engl. J. Med. 368, 623–632 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Janne, 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).

    Article  CAS  PubMed  Google Scholar 

  55. Shapiro, G. 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 [abstract]. J. Clin. Oncol. 29 (Suppl.), a3005 (2011).

    Article  Google Scholar 

  56. 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).

    Article  CAS  PubMed  Google Scholar 

  57. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Renouf, D. J., Velazquez-Martin, J. P., Simpson, R., Siu, L. L. & Bedard, P. L. Ocular toxicity of targeted therapies. J. Clin. Oncol. 30, 3277–3286 (2012).

    Article  CAS  PubMed  Google Scholar 

  59. Chen, X., Schwartz, G. K., DeAngelis, L. M., Kaley, T. & Carvajal, R. D. Dropped head syndrome: report of three cases during treatment with a MEK inhibitor. Neurology 79, 1929–1931 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Cohen, R. B. et al. A phase I dose-finding, safety and tolerability study of AZD8330 in patients with advanced malignancies. Eur. J. Cancer 49, 1521–1529 (2013).

    Article  CAS  PubMed  Google Scholar 

  61. Borad, M. J. et al. Phase I dose-escalation study of E6201, a MEK-1 inhibitor, in advanced solid tumors [abstract]. J. Clin. Oncol. 28 (Suppl.), a2505 (2010).

    Article  Google Scholar 

  62. Sequist, L. V. et al. First-in-human evaluation of CO-1686, an irreversible, selective, and potent tyrosine kinase inhibitor of EGFR T790M [abstract]. J. Clin. Oncol. 31 (Suppl.), a2524 (2013).

    Google Scholar 

  63. Mehra, R. et al. First-in-human phase I study of the ALK inhibitor LDK378 in advanced solid tumors [abstract]. J. Clin. Oncol. 30 (Suppl.), a3007 (2012).

    Google Scholar 

  64. Camidge, D. R. et al. First-in-human dose-finding study of the ALK/EGFR inhibitor AP26113 in patients with advanced malignancies: updated results [abstract]. J. Clin. Oncol. 31 (Suppl.), a8031 (2013).

    Google Scholar 

  65. Harding, J. J. et al. Vemurafenib (VEM) in patients (pts) with BRAF-mutant melanoma and brain metastases (mets) [abstract]. J. Clin. Oncol. 31 (Suppl.), a9060 (2013).

    Google Scholar 

  66. Long, G. V. et al. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol. 13, 1087–1095 (2012).

    Article  CAS  PubMed  Google Scholar 

  67. Barrett, S. D. et al. The discovery of the benzhydroxamate MEK inhibitors CI-1040 and PD 0325901. Bioorg. Med. Chem. Lett. 18, 6501–6504 (2008).

    Article  CAS  PubMed  Google Scholar 

  68. Sebolt-Leopold, J. S. et al. The biological profile of PD 0325901: a second generation analog of CI-1040 with improved pharmaceutical potential [abstract]. Proc. Amer. Assoc. Cancer Res. 45, a4003 (2004).

    Google Scholar 

  69. Huang, W. et al. PD0325901, a mitogen-activated protein kinase kinase inhibitor, produces ocular toxicity in a rabbit animal model of retinal vein occlusion. J. Ocul. Pharmacol. Ther. 25, 519–530 (2009).

    Article  CAS  PubMed  Google Scholar 

  70. Haura, E. B. 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. 16, 2450–2457 (2010).

    Article  CAS  PubMed  Google Scholar 

  71. Britten, C. et al. Multi-arm phase 1 dose escalation study of safety, pharmacokinetics, and pharmacodynamics of the dual PI3K/mTOR inhibitors PF-04691502 (oral) and PF-05212384 (IV) in combination with the MEK inhibitor PD-0325901 or irinotecan in patients with advanced cancer. Eur. J. Cancer 48, 109 (2012).

    Article  Google Scholar 

  72. 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).

    Article  CAS  PubMed  Google Scholar 

  73. Haass, N. K. et al. The mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor AZD6244 (ARRY-142886) induces growth arrest in melanoma cells and tumor regression when combined with docetaxel. Clin. Cancer Res. 14, 230–239 (2008).

    Article  CAS  PubMed  Google Scholar 

  74. Davies, B. R. et al. AZD6244 (ARRY-142886), a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 kinases: mechanism of action in vivo, pharmacokinetic/pharmacodynamic relationship, and potential for combination in preclinical models. Mol. Cancer Ther. 6, 2209–2219 (2007).

    Article  CAS  PubMed  Google Scholar 

  75. Huynh, H., Soo, K. C., Chow, P. K. & Tran, E. Targeted inhibition of the extracellular signal-regulated kinase kinase pathway with AZD6244 (ARRY-142886) in the treatment of hepatocellular carcinoma. Mol. Cancer Ther. 6, 138–146 (2007).

    Article  CAS  PubMed  Google Scholar 

  76. 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).

    Article  CAS  PubMed  Google Scholar 

  77. 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).

    Article  CAS  PubMed  Google Scholar 

  78. Catalanotti, F. et al. Phase II trial of MEK inhibitor selumetinib (AZD6244) in patients with BRAFV600E/K-mutated melanoma. Clin. Cancer Res. 19, 2257–2264 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Hayes, D. N. 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. 18, 2056–2065 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. O'Neil, B. H. et al. Phase II study of the mitogen-activated protein kinase 1/2 inhibitor selumetinib in patients with advanced hepatocellular carcinoma. J. Clin. Oncol. 29, 2350–2356 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Jain, N, C. et al. Phase II study of the oral MEK inhibitor selumetinib (AZD6244) in advanced acute myeloid leukemia (AML) [abstract]. J. Clin. Oncol. 30 (Suppl.), a6582 (2012).

    Google Scholar 

  82. Khan, K. H. et al. A phase I dose escalation study of oral MK-2206 (allosteric Akt inhibitor) with oral selumetinib (AZD6244; ARRY-142866) (MEK 1/2 inhibitor) in patients with advanced or metastatic solid tumors. J. Clin. Oncol. 28, e13599 (2012).

    Google Scholar 

  83. Kirkwood, J. M. 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. 18, 555–567 (2012).

    Article  CAS  PubMed  Google Scholar 

  84. 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).

    Article  PubMed  Google Scholar 

  85. Bodoky, 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).

    Article  CAS  PubMed  Google Scholar 

  86. 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).

    Article  CAS  PubMed  Google Scholar 

  87. 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).

    Article  CAS  PubMed  Google Scholar 

  88. Deming, D. A. 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) [abstract]. J. Clin. Oncol. 30 (Suppl.), a3103 (2012).

    Google Scholar 

  89. Durante, C. et al. BRAF mutations in papillary thyroid carcinomas inhibit genes involved in iodine metabolism. J. Clin. Endocrinol. Metab. 92, 2840–2843 (2007).

    Article  CAS  PubMed  Google Scholar 

  90. Knauf, J. A., Kuroda, H., Basu, S. & Fagin, J. A. RET/PTC-induced dedifferentiation of thyroid cells is mediated through Y1062 signaling through SHC–Ras–MAP kinase. Oncogene 22, 4406–4412 (2003).

    Article  CAS  PubMed  Google Scholar 

  91. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  92. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  93. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  94. Hochster, H. S. 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) [abstract]. J. Clin. Oncol. 31 (Suppl.), a3587 (2013).

    Google Scholar 

  95. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  96. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  97. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  98. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  99. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  100. Gupta, 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 [abstract]. J. Clin. Oncol. 31 (Suppl.), a9068 (2013).

    Google Scholar 

  101. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  102. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  103. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  104. Rice, K. D. et al. Novel carboxamide-based allosteric MEK inhibitors: discovery and optimization efforts toward XL518 (GDC-0973). ACS Med. Chem. Lett. 3, 416–421 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Fremin, C. & Meloche, S. From basic research to clinical development of MEK1/2 inhibitors for cancer therapy. J. Hematol. Oncol. 3, 8 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Rosen, L. S. et al. A phase 1 dose-escalation study of XL518, a potent MEK inhibitor administered orally daily to subjects with solid tumors [abstract]. J. Clin. Oncol. 26 (Suppl.), a14585 (2008).

    Article  Google Scholar 

  107. 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 [abstract]. J. Clin. Oncol. 30 (Suppl.), a2566 (2012).

    Google Scholar 

  108. Villanueva, J. et al. Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K. Cancer Cell 18, 683–695 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Nazarian, R. et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 468, 973–977 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Johannessen, C. M. et al. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 468, 968–972 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Gonzalez, R. et al. Phase ib study of vemurafenib in combination with the MEK inhibitor, GDC-0973, in patients (pts) with unresectable or metastatic BRAFV600 mutated melanoma (BRIM7) [abstract 2744]. Presented at the 37th ESMO congress 2012.

  112. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  113. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  114. 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).

    Article  CAS  PubMed  Google Scholar 

  115. 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).

    Article  CAS  PubMed  Google Scholar 

  116. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  118. Whittaker, S., Marais, R. & Zhu, A. X. The role of signaling pathways in the development and treatment of hepatocellular carcinoma. Oncogene 29, 4989–5005 (2010).

    Article  CAS  PubMed  Google Scholar 

  119. Lim, H. 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) [abstract]. J. Clin. Oncol. 30 (Suppl.), a4103 (2012).

    Google Scholar 

  120. Van Laethem, J. L. 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 [abstract]. J. Clin. Oncol. 30 (Suppl.), a4050 (2012).

    Google Scholar 

  121. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  122. 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).

    Article  CAS  PubMed  Google Scholar 

  123. 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).

    Article  CAS  PubMed  Google Scholar 

  124. US Food and Drug Administration. Vemurafenib [online], (2011).

  125. Eggermont, A. M. & Robert, C. New drugs in melanoma: it's a whole new world. Eur. J. Cancer 47, 2150–2157 (2011).

    Article  PubMed  Google Scholar 

  126. US Food and Drug Administration. Dabrafenib [online], (2013).

  127. 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).

    Article  CAS  PubMed  Google Scholar 

  128. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  129. US Food and Drug Administration. Trametinib and Dabrafenib [online], (2014).

  130. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  131. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  132. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  133. Infante, J. R. 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 [abstract]. J. Clin. Oncol. 30 (Suppl.), a291 (2013).

    Article  Google Scholar 

  134. 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 [abstract]. J. Clin. Oncol. 30 (Suppl.), a3023 (2012).

    Google Scholar 

  135. Ahmed, S. R. et al. A phase I study determining the safety and tolerability of combination therapy with pazopanib, a VEGFR/PDGFR/raf inhibitor, and GSK1120212, a MEK inhibitor, in advanced solid tumors enriched with patients with advanced differentiated thyroid cancer [abstract]. J. Clin. Oncol. 30 (Suppl.), TPS3117 (2012).

    Google Scholar 

  136. Infante, J. R. et al. A phase Ib study of the MEK inhibitor GSK1120212 combined with everolimus in patients with solid tumors: interim results [abstract]. Mol. Cancer Ther. 10 (Suppl. 1), B128 (2011).

    Google Scholar 

  137. 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) [abstract]. J. Clin. Oncol. 29 (Suppl.), a3085 (2011).

    Article  Google Scholar 

  138. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  139. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  140. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  141. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  142. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  143. US National Library of Medicine. ClinicalTrials.gov[online],1 (2014).

  144. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Delord, J. et al. First-in-human phase I safety, pharmacokinetic (PK), and pharmacodynamic (PD) analysis of the oral MEK-inhibitor AS703026 (two regimens [R]) in patients (pts) with advanced solid tumors [abstract]. J. Clin. Oncol. 28 (Suppl.), a2504 (2010).

    Article  Google Scholar 

  146. Houede, N. et al. Safety and evidence of activity of MSC1936369, an oral MEK1/2 inhibitor, in patients with advanced malignancies [abstract]. J. Clin. Oncol. 29 (Suppl.), a3019 (2011).

    Article  Google Scholar 

  147. Macarulla, T. 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. 23 iv19–iv30 (2012).

    Article  Google Scholar 

  148. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  149. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  150. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  151. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  152. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  153. Bendell, J. C. et al. A phase I dose-escalation study of MEK inhibitor MEK162 (ARRY-438162) in patients with advanced solid tumors [abstract]. Mol. Cancer Ther. 10 (Suppl. 1), B243 (2011).

    Google Scholar 

  154. Richard, S. et al. A phase I study of MEK inhibitor MEK162 (ARRY-438162) in patients with biliary tract cancer [abstract]. J. Clin. Oncol. 30 (Suppl.), a220 (2012).

    Google Scholar 

  155. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  156. 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).

    Article  CAS  PubMed  Google Scholar 

  157. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  158. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  159. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  160. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  161. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  162. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  163. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  164. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  165. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  166. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  167. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  168. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  169. Wallace, E. et al. AZD8330 (ARRY-424704): preclinical evaluation of a potent, selective MEK 1/2 inhibitor currently in phase I trials [abstract 3696]. Presented at the AACR 100th Annual Meeting 2009.

  170. 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).

    Article  CAS  PubMed  Google Scholar 

  171. 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).

    Article  CAS  PubMed  Google Scholar 

  172. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. 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).

    Article  CAS  PubMed  Google Scholar 

  174. Mala, C. et al. A phase I, first-in-human single ascending dose study of the MEK inhibitor WX-554 given to healthy male subjects [abstract]. J. Clin. Oncol. 28 (Suppl.), e13666 (2010).

    Article  Google Scholar 

  175. Sosman, J. A. et al. First-in-human, multicenter, dose-escalation, phase I study of the investigational drug TAK-733, an oral MEK inhibitor, in patients (pts) with advanced nonhematologic malignancies and melanoma [abstract]. J. Clin. Oncol. 29 (Suppl.), TPS145 (2011).

    Article  Google Scholar 

  176. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  177. US National Library of Medicine. ClinicalTrials.gov[online], (2012).

  178. 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 [abstract]. Mol. Cancer Ther. 12, B75 (2013).

    Article  CAS  Google Scholar 

  179. Adjei, A. A. et al. Phase I, dose-escalation study of the investigational drug TAK-733, an oral MEK inhibitor, in patients (pts) with advanced solid tumors [abstract]. J. Clin. Oncol. 31 (Suppl.), a2528 (2013).

    Google Scholar 

  180. Hatzivassiliou, G. et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 464, 431–435 (2010).

    Article  CAS  PubMed  Google Scholar 

  181. Hatzivassiliou, G. et al. Mechanism of MEK inhibition determines efficacy in mutant KRAS- versus BRAF-driven cancers. Nature 501, 232–236 (2013).

    Article  CAS  PubMed  Google Scholar 

  182. Jing, J. et al. Comprehensive predictive biomarker analysis for MEK inhibitor GSK1120212. Mol. Cancer Ther. 11, 720–729 (2012).

    Article  CAS  PubMed  Google Scholar 

  183. Dry, J. R. et al. Transcriptional pathway signatures predict MEK addiction and response to selumetinib (AZD6244). Cancer Res. 70, 2264–2273 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Gore, L. 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 [abstract]. J. Clin. Oncol. 29 (Suppl.), a3007 (2011).

    Article  Google Scholar 

  185. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  186. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  187. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  188. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  189. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  190. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  191. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  192. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  193. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  194. US National Library of Medicine. ClinicalTrials.gov[online], (2012).

  195. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  196. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  197. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  198. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  199. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  200. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  201. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  202. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  203. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  204. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  205. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  206. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  207. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  208. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  209. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

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Acknowledgements

The work of A.A.A. is supported by a Drug Development Research Professorship from the American Society of Clinical Oncology Conquer Cancer Foundation.

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  1. Department of Medicine, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, 14263, NY, USA

    Yujie Zhao & Alex A. Adjei

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Both authors researched the data for the article, provided a substantial contribution to discussions of the content, wrote the article, and reviewed and edited the manuscript before submission.

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Zhao, Y., Adjei, A. The clinical development of MEK inhibitors. Nat Rev Clin Oncol 11, 385–400 (2014). https://doi.org/10.1038/nrclinonc.2014.83

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