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  • Review Article
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MEK1 and MEK2 inhibitors and cancer therapy: the long and winding road

Nature Reviews Cancer volume 15, pages 577–592 (2015)Cite this article

Subjects

Key Points

  • The RAS-regulated RAF–MEK–ERK signalling pathway transmits signals from growth factor receptors to the nucleus and other organelles to regulate cell proliferation, differentiation, survival and invasion.

  • ERK pathway architecture places MEK1 and MEK2 in a unique position, where they process inputs from multiple upstream activating kinases so that ERK1 and ERK2 may be activated alone (following RAF activation) or together with other kinases such as JNK or p38.

  • The majority of cancers exhibit hyper-activation of the ERK pathway owing to deregulation (mutation, gene fusions, amplification, and so on) of receptor tyrosine kinases, RAS, BRAF, CRAF, MEK1 or MEK2 or owing to the loss of negative pathway regulators, such as dual-specificity phosphatases (DUSPs) and NF1. In many cases, these mutations confer a range of pathway dependencies including classical 'oncogene addiction', providing a rationale for ERK pathway inhibitors as therapeutic agents.

  • Melanomas carrying the mutation encoding BRAF-V600E are almost invariably addicted to BRAF activity, and first-generation BRAF inhibitors (BRAFis) have transformed the treatment of this disease. However, an inability to inhibit signalling by RAF dimers drives acquired resistance, and paradoxical RAF activation in tumours with wild-type BRAF limits the success or wider application of BRAFis.

  • As RAF signalling proceeds via the activation of MEK1 and MEK2, and RAF-addicted tumour cells are also MEK-addicted, MEK1 and MEK2 are also attractive drug targets. Additionally, MEK1 and MEK2 contain a unique hydrophobic pocket adjacent to their ATP-binding site, which allows the binding of potent, non-ATP competitive, allosteric inhibitors. However, MEK1 and MEK2 are rarely mutated in cancer, so MEK inhibitors (MEKis) will not preferentially inhibit MEK1 and MEK2 in tumour cells compared with normal tissue; this may contribute to normal tissue toxicity.

  • The first MEKi to receive US Food and Drug Administration approval, trametinib, is being used to treat BRAF-mutant melanoma in combination with first-generation BRAFis. A range of additional MEKis are in late-stage clinical development and exhibit various modes of action; for example, some MEKis can prevent the phosphorylation of MEK1 and MEK2 by RAF, and others can disrupt RAF–MEK1/MEK2 complexes. The extent to which these properties influence clinical activity is currently unclear.

  • Factors that limit the efficacy of MEKis include loss of feedback inhibition and consequent reactivation of ERK1 and ERK2. Intrinsic resistance can be driven by the activation of parallel pathways, including the PI3K pathway, whereas acquired resistance to MEKis arises through the emergence of mutations in MEK1 or MEK2 or the amplification of BRAFV600E or mutant RAS.

  • Adaptation and resistance to MEKis can be overcome by combinations with other targeted agents, including intrapathway dual inhibition. Clinical trials assessing MEKis in combination with other targeted agents or conventional chemotherapy are ongoing.

Abstract

The role of the ERK signalling pathway in cancer is thought to be most prominent in tumours in which mutations in the receptor tyrosine kinases RAS, BRAF, CRAF, MEK1 or MEK2 drive growth factor-independent ERK1 and ERK2 activation and thence inappropriate cell proliferation and survival. New drugs that inhibit RAF or MEK1 and MEK2 have recently been approved or are currently undergoing late-stage clinical evaluation. In this Review, we consider the ERK pathway, focusing particularly on the role of MEK1 and MEK2, the 'gatekeepers' of ERK1/2 activity. We discuss their validation as drug targets, the merits of targeting MEK1 and MEK2 versus BRAF and the mechanisms of action of different inhibitors of MEK1 and MEK2. We also consider how some of the systems-level properties (intrapathway regulatory loops and wider signalling network connections) of the ERK pathway present a challenge for the success of MEK1 and MEK2 inhibitors, discuss mechanisms of resistance to these inhibitors, and review their clinical progress.

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Figure 1: Scaffolds and feedback controls underpin the normal functioning of the ERK1/2 pathway.
Figure 2: MEK1 and MEK2 are the key 'gatekeepers' for ERK1 and ERK2 in a wider signalling network.
Figure 3: Linear representation of the key functional domains of the human MEK1 and MEK2 proteins.
Figure 4: MEKis that inhibit MEK1/2 phosphorylation suppress the rebound in ERK1/2 activation that results from relief of negative feedback.
Figure 5: Adaptive kinome reprograming arising from MEK1/2 inhibition.
Figure 6: Mechanisms of acquired resistance to MEK1/2 inhibitors (MEKis).

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References

  1. Yoon, S. & Seger, R. The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions. Growth Factors 24, 21–44 (2006).

    Article  CAS  PubMed  Google Scholar 

  2. Karnoub, A. E. & Weinberg, R. A. Ras oncogenes: split personalities. Nat. Rev. Mol. Cell Biol. 9, 517–531 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. von Kriegsheim, A. et al. Cell fate decisions are specified by the dynamic ERK interactome. Nat. Cell Biol. 11, 1458–1464 (2009).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  5. Balmanno, K. & Cook, S. J. Tumour cell survival signalling by the ERK1/2 pathway. Cell Death Differ. 16, 368–377 (2009).

    Article  CAS  PubMed  Google Scholar 

  6. Bromberg-White, J. L., Andersen, N. J. & Duesbery, N. S. MEK genomics in development and disease. Brief. Funct. Genom. 11, 300–310 (2012).

    Article  CAS  Google Scholar 

  7. Ying, Q. L. et al. The ground state of embryonic stem cell self-renewal. Nature 453, 519–523 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).

    Article  CAS  PubMed  Google Scholar 

  9. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation Cell 144, 646–674 (2011).

    Article  CAS  PubMed  Google Scholar 

  10. Sebolt-Leopold, J. S. & Herrera, R. Targeting the mitogen-activated protein kinase cascade to treat cancer. Nat. Rev. Cancer. 4, 937–947 (2004).

    Article  CAS  PubMed  Google Scholar 

  11. Montagut, C. & Settleman, J. Targeting the RAF–MEK–ERK pathway in cancer therapy. Cancer Lett. 283, 125–134 (2009).

    Article  CAS  PubMed  Google Scholar 

  12. Samatar, A. A. & Poulikakos, P. I. Targeting RAS–ERK signalling in cancer: promises and challenges. Nat. Rev. Drug Discov. 13, 928–942 (2014).

    Article  CAS  PubMed  Google Scholar 

  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). This is the first report of a small-molecule inhibitor of MEK1/2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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). This is the first paper to demonstrate that a potent and specific allosteric MEK1/2 inhibitor could inhibit the growth of tumour xenografts in vivo.

    Article  CAS  PubMed  Google Scholar 

  15. Frémin, 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 

  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). This study provides a detailed characterization of trametinib, the first MEK1/2 inhibitor to receive US Food and Drug Administration (FDA) approval.

    Article  CAS  PubMed  Google Scholar 

  17. Davies, H. et al. Mutations of the BRAF gene in human cancer. Nature 417, 949–954 (2002). This paper provides the first description of activating mutations in BRAF in human cancer, including the particularly high incidence in melanoma.

    Article  CAS  PubMed  Google Scholar 

  18. Bollag, G. et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature 467, 596–599 (2010). This is the first study that attempted to systematically quantify the extent of RAF–MEK–ERK suppression required for effective tumour suppression.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Bollag, G. Vemurafenib: the first drug approved for BRAF-mutant cancer. Nat. Rev. Drug Discov. 11, 873–886 (2012).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ramos, J. W. The regulation of extracellular signal-regulated kinase (ERK) in mammalian cells. Int. J. Biochem. Cell Biol. 40, 2707–2719 (2008).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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). The elegant quantitative proteomics approach used in this study reveals the extent of adaptive reprogramming induced by MEK inhibition.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Johannessen, C. M. et al. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 468, 968–972 (2010). This is the first demonstration of an alternative, non-RAF 'MEK1/2 activator' driving BRAFi resistance.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  36. Roskoski, R. MEK1/2 dual-specificity protein kinases: structure and regulation. Biochem. Biophys. Res. Commun. 417, 5–10 (2012).

    Article  CAS  PubMed  Google Scholar 

  37. Procaccia, S. & Seger, R. in Encyclopedia of Signaling Molecules (ed. Choi, S.) 1051–1058 (Springer, 2012).

    Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Alessi, D. R. Identification of the sites in MAP kinase kinase-1 phosphorylated by p74raf-1. EMBO J. 13, 1610–1619 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  43. Bélanger, L. F. et al. Mek2 is dispensable for mouse growth and development. Mol. Cell. Biol. 23, 4778–4787 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  46. Mansour, S. J. et al. Transformation of mammalian cells by constitutively active MAP kinase kinase. Science 265, 966–970 (1994). This paper, along with reference 45, demonstrated that phosphomimetic mutations in the activation loop caused constitutive activation of MEK1; the 'activated' MEK1 served as an oncogene when expressed in cells.

    Article  CAS  PubMed  Google Scholar 

  47. Solit, D. B. et al. BRAF mutation predicts sensitivity to MEK inhibition. Nature 439, 358–362 (2006). This paper studied a panel of human cancer cell lines and showed that BRAF-mutated cells tended to be far more sensitive to MEK inhibition (addicted to MEK1/2) than those harbouring RAS mutations.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Heidorn, S. J. et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell 140, 209–221 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. 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 

  53. Holderfield, M. et al. RAF inhibitors activate the MAPK pathway by relieving inhibitory autophosphorylation. Cancer Cell 23, 594–602 (2013). The studies in references 50–53 identified the biochemical bases for paradoxical RAF activation by BRAFi, highlighting the need for MEK inhibition for more stable pathway inhibition.

    Article  CAS  PubMed  Google Scholar 

  54. Rodriguez-Viciana, P. et al. Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome. Science 311, 1287–1290 (2006).

    Article  CAS  PubMed  Google Scholar 

  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). This is the first report of mutations in MEK1 or MEK2 in human cancer.

    Article  CAS  PubMed  Google Scholar 

  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). This is the first report of activating MEK1 or MEK2 mutations in human cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  59. Nikolaev, S. I. et al. Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma. Nat. Genet. 44, 133–139 (2011).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Karreth, F. A., 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  64. Favata, M. F. et al. Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J. Biol. Chem. 273, 18623–18632 (1998).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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). The structural studies of MEK1 and MEK2 in this paper reveal the presence of a unique allosteric inhibitor binding pocket adjacent to, but distinct from, the ATP-binding site; this pocket is the binding site for the allosteric MEKis.

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  69. 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 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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). This is the first publication showing that MEKis cause potent MEK1/2 phosphorylation owing to 'feedback relief'.

    Article  CAS  PubMed  Google Scholar 

  74. 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 

  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). This paper and reference 74 demonstrate that newer 'feedback buster' MEKis prevent the MEK1/2 phosphorylation and associated ERK1/2 rebound arising from 'feedback relief', providing more durable suppression of KRAS-mutant tumour growth.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  80. Dickson, M. A. Molecular pathways: CDK4 inhibitors for cancer therapy. Clin. Cancer Res. 20, 3379–3383 (2014).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  PubMed  PubMed Central  Google Scholar 

  86. Kwong, L. N. et al. Oncogenic NRAS signaling differentially regulates survival and proliferation in melanoma. Nat. Med. 18, 1503–1510 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Tolcher, A. W. et al. Antitumor activity in RAS-driven tumors by blocking AKT and MEK. Clin. Cancer Res. 21, 739–748 (2015).

    Article  CAS  PubMed  Google Scholar 

  92. Dai, B. et al. STAT3 mediates resistance to MEK inhibitor through microRNA miR-17. Cancer Res. 71, 3658–3668 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Lin, L. et al. The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies. Nat. Genet. 47, 250–256 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. 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 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Lee, H. J. et al. Drug resistance via feedback activation of Stat3 in oncogene-addicted cancer cells. Cancer Cell 26, 207–221 (2014).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Little, A. S., Smith, P. D. & Cook, S. J. Mechanisms of acquired resistance to ERK1/2 pathway inhibitors. Oncogene 32, 1207–1215 (2013).

    Article  CAS  PubMed  Google Scholar 

  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). This is the first report of acquired resistance to allosteric MEKis; in this case an emergent MEK1 mutation in a patient treated with selumetinib.

    Article  PubMed  PubMed Central  Google Scholar 

  103. Hatzivassiliou, G. et al. ERK inhibition overcomes acquired resistance to MEK inhibitors. Mol. Cancer Ther. 11, 1143–1154 (2012).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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). This report and reference 106 demonstrate that amplification of BRAFV600E can drive acquired resistance to MEKis, which can be overcome by dual RAF and MEK inhibition. This paper additionally demonstrates that KRAS amplification can also drive MEKi resistance.

    Article  CAS  PubMed  Google Scholar 

  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). This is a key clinical proof-of-principle study demonstrating the potential of dual RAF and MEK inhibition to cause more durable tumour suppression.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  117. Robert, C. et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N. Engl. J. Med. 372, 30–39 (2015).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  PubMed  PubMed Central  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  131. Jones, D. T. W. et al. Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma Nat. Genet. 45, 927–932 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  134. Chen, Z. et al. A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response. Nature 483, 613–617 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. 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 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  147. Chapman, P. B. et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N. Engl. J. Med. 364, 2507–2516 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Zhao, Y. & Adjei, A. A. The clinical development of MEK inhibitors. Nat. Rev. Clin. Oncol. 11, 385–400 (2014).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Google Scholar 

  154. Pratilas, C. A. et al. Genetic predictors of MEK dependence in non-small cell lung cancer. Cancer Res. 68, 9375–9383 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Google Scholar 

  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). This is a case study highlighting the use of combined BRAFis and MEKis to control both target BRAF-mutant melanoma and prevent paradoxical acceleration of incipient RAS-mutant tumours.

    Article  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  159. Lamba, S. et al. RAF suppression synergizes with MEK inhibition in KRAS mutant cancer cells. Cell Rep. 8, 1475–1483 (2014).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  166. Sturm, O. E. et al. The mammalian MAPK/ERK pathway exhibits properties of a negative feedback amplifier. Sci. Signal 3, ra90 (2010). This study uses simplified mathematical models of negative feedback in the RAF–MEK–ERK cascade coupled with wet-laboratory data to explain resistance to inhibition in normality and why BRAF mutations render the cascade more susceptible to inhibition.

    Article  CAS  PubMed  Google Scholar 

  167. Heinrich, R., Neel, B. G. & Rapoport, T. A. Mathematical models of protein kinase signal transduction. Mol. Cell 9, 957–970 (2002).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  170. Kholodenko, B. N., Hancock, J. F. & Kolch, W. Signalling ballet in space and time. Nat. Rev. Mol. Cell Biol. 11, 414–426 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Rajakulendran, T., Sahmi, M., Lefrançois, M., Sicheri, F. & Therrien, M. A dimerization-dependent mechanism drives RAF catalytic activation. Nature 461, 542–545 (2009).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  175. Fritsche-Guenther, R. et al. Strong negative feedback from Erk to Raf confers robustness to MAPK signalling. Mol. Syst. Biol. 7, 489 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. McKay, M. M. & Morrison, D. K. Integrating signals from RTKs to ERK/MAPK. Oncogene 26, 3113–3121 (2007).

    Article  CAS  PubMed  Google Scholar 

  177. Yarden, Y. & Slikowski, M. X. Untangling the ErbB signalling network. Nat. Revs Mol. Cell. Biol. 2, 127–137 (2001).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Mielgo, A. et al. A MEK-independent role for CRAF in mitosis and tumor progression. Nat. Med. 17, 1641–1645 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  182. Lee, P. A. et al. Preclinical development of ARRY-162, a potent and selective MEK 1/2 inhibitor. Cancer Res. 70, S2515 (2010).

    Google Scholar 

  183. Chen, X. et al. Combined PKC and MEK inhibition in uveal melanoma with GNAQ and GNA11 mutations. Oncogene 33, 4724–4734 (2014).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  Google Scholar 

  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], (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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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], (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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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Acknowledgements

The authors thank J. Sebolt-Leopold who provided information as a personal communication and apologize to those whose work was not included owing to space limitations.

Author information

Authors and Affiliations

  1. Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath, BA2 7AY, UK

    Christopher J. Caunt

  2. Signalling Laboratory, The Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT, UK

    Matthew J. Sale & Simon J. Cook

  3. AstraZeneca, Oncology iMed, Cancer Biosciences, Cancer Research UK, Li Ka Shing Centre, Cambridge Institute, Robinson Way, Cambridge, CB2 0RE, UK

    Paul D. Smith

Authors
  1. Christopher J. Caunt
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  2. Matthew J. Sale
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Corresponding authors

Correspondence to Paul D. Smith or Simon J. Cook.

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Competing interests

P.D.S. is a paid employee and shareholder of AstraZeneca. Some work in S.J.C.'s laboratory is supported by a sponsored research collaboration funded by AstraZeneca; however, S.J.C. receives no personal payment of any kind from AstraZeneca. C.J.C. and M.J.S. declare no competing interests.

Supplementary information

41568_2015_BFnrc4000_MOESM215_ESM.pdf

Supplementary information S1 (figure) | Whilst RAF proteins were the first 'MEK activators' to be described, they are a subset of the MEK activators in cells. (PDF 309 kb)

PowerPoint slides

Glossary

2i

A cocktail of two protein kinase inhibitors, one inhibiting MEK1 and MEK2, and the other inhibiting glycogen synthase kinase 3 (GSK3).

Allosteric inhibitor

A small molecule that inhibits the activity of an enzyme by binding to a regulatory site that is distinct from the active or catalytic site.

MEK addiction

How dependent on MEK1/2 activity a tumour cell is for survival and proliferation; it can broadly be measured by how sensitive a tumour cell is to a MEK inhibitor.

Feedback relief

ERK1/2-catalysed feedback phosphorylation and inhibition of RAF normally operates in the pathway but is relieved when MEK1/2 are inhibited and ERK1/2 activity declines, resulting in the activation of RAF and further MEK1/2 phosphorylation. Pathway activity also stimulates the expression of negative regulators of pathway activity such as the ERK phosphatase DUSP6; expression of these negative regulators is reduced when the pathway is inhibited.

Feedback buster

A term adopted by the field, although something of a misnomer. All MEK inhibitors (MEKis) relieve ERK-dependent negative feedback to RAF, resulting in RAF activation. Feedback buster MEKis mitigate some, but not all, consequences of feedback relief that arise when ERK is inhibited by interfering with the phosphorylation of MEK by RAF, thereby reducing rebound activation of the pathway. By contrast, conventional MEKis do not prevent MEK phosphorylation by RAF.

Phosphomimetic mutant

A phosphomimetic mutant of MEK1 exhibits constitutive (MAP3K-independent) activation owing to acidic substitutions at Ser218 and Ser222 in the activation loop that mimic the negative charge of phosphorylation.

Dacarbazine

A DNA-alkylating agent that has commonly been used as a single agent in the treatment of metastatic melanoma.

Plexiform neurofibromatosis

A non-cancerous hyperproliferative disease of the nerve sheath that is driven by the loss of the NF1 tumour suppressor.

Neoadjuvant

A neoadjuvant therapy is treatment given before primary therapy; in the context of this Review, selumetinib is administered first as adjuvant therapy and continued until the radioactive iodine therapy has been administered.

RASness

Refers to a transcriptomic signature that reports activation of the RAS pathway and may predict responses to RAS pathway drugs.

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Caunt, C., Sale, M., Smith, P. et al. MEK1 and MEK2 inhibitors and cancer therapy: the long and winding road. Nat Rev Cancer 15, 577–592 (2015). https://doi.org/10.1038/nrc4000

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