Targeting mutant NRAS signaling pathways in melanoma

Pharmacological Research

Volumn 107, Issue , 2016, Pages 111-116

  Vu, Ha Linh ^a   Aplin, Andrew E ^a  

^a THOMAS JEFFERSON UNIVERSITY   (United States)

Author keywords

Melanoma; NRAS; PI3K; RAF; Ral GEF; Targeted inhibitors

Indexed keywords

CYCLIN DEPENDENT KINASE 4; CYCLIN DEPENDENT KINASE 6; EPIDERMAL GROWTH FACTOR RECEPTOR; GUANOSINE TRIPHOSPHATASE; I KAPPA B KINASE; MITOGEN ACTIVATED PROTEIN KINASE; MITOGEN ACTIVATED PROTEIN KINASE KINASE; MITOGEN ACTIVATED PROTEIN KINASE KINASE INHIBITOR; PHOSPHATIDYLINOSITOL 3 KINASE; POLO LIKE KINASE 1; PROTEIN KINASE B; PROTEIN SERINE THREONINE KINASE INHIBITOR; RAF INHIBITOR; RAF PROTEIN; RAL PROTEIN; RHO KINASE; TANK BINDING KINASE 1; UNCLASSIFIED DRUG; PROTEIN KINASE; PROTEIN KINASE INHIBITOR; RAS PROTEIN;

CANCER CELL; CANCER COMBINATION CHEMOTHERAPY; CUTANEOUS MELANOMA; ENZYME ACTIVATION; ENZYME INHIBITION; HUMAN; MOLECULARLY TARGETED THERAPY; MONOTHERAPY; MUTANT; NONHUMAN; ONCOGENE N RAS; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION; ANIMAL; GENETICS; MELANOMA; METABOLISM; MUTATION; SKIN NEOPLASMS;

ANIMALS; HUMANS; MELANOMA; MUTATION; PROTEIN KINASE INHIBITORS; PROTEIN KINASES; RAS PROTEINS; SIGNAL TRANSDUCTION; SKIN NEOPLASMS;

EID: 84961792748     PISSN: 10436618     EISSN: 10961186     Source Type: Journal    
DOI: 10.1016/j.phrs.2016.03.007     Document Type: Review

References (90)

1. M. Amano, M. Nakayama, and K. Kaibuchi Rho-kinase/ROCK: A key regulator of the cytoskeleton and cell polarity Cytoskeleton 67 2010 545 554
2. P.A. Ascierto, D. Schadendorf, C. Berking, S.S. Agarwala, C.M. van Herpen, P. Queirolo, and 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 2013 249 256
3. M. Atefi, B. Titz, E. Avramis, C. Ng, D.J. Wong, A. Lassen, and et al. Combination of pan-RAF and MEK inhibitors in NRAS mutant melanoma Mol. Cancer 14 27 2015 015-0293-5
4. D.A. Barbie, P. Tamayo, J.S. Boehm, S.Y. Kim, S.E. Moody, I.F. Dunn, and et al. Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1 Nature 462 2009 108 112
5. J.C. Bendell, K. Papadopoulos, S.F. Jones, E. Barrett, K. Guthrie, C.L. Kass, et al., Phase 1 dose-escalation study of MEK inhibitor MEK162 (ARRY-438162) in patients with advanced solid tumors. AACR-NCI-EORTC (abstr B243).
6. G. Buhrman, G. Holzapfel, S. Fetics, and C. Mattos Allosteric modulation of ras positions Q61 for a direct role in catalysis Proc. Natl. Acad. Sci. U. S. A. 107 2010 4931 4936
7. E. Castellano, C. Sheridan, M.Z. Thin, E. Nye, B. Spencer-Dene, M.E. Diefenbacher, and et al. Requirement for interaction of PI3-kinase p110alpha with RAS in lung tumor maintenance Cancer Cell 24 2013 617 630
8. Y. Chien, S. Kim, R. Bumeister, Y.M. Loo, S.W. Kwon, C.L. Johnson, and et al. RalB GTPase-mediated activation of the IkappaB family kinase TBK1 couples innate immune signaling to tumor cell survival Cell 127 2006 157 170
9. B.D. Cholewa, M.C. Pellitteri-Hahn, C.O. Scarlett, and N. Ahmad Large-scale label-free comparative proteomics analysis of polo-like kinase 1 inhibition via the small-molecule inhibitor BI 6727 (volasertib) in BRAF(V600E) mutant melanoma cells J. Proteome Res. 13 2014 5041 5050
10. M. Colombino, M. Capone, A. Lissia, A. Cossu, C. Rubino, V. De Giorgi, and et al. BRAF/NRAS mutation frequencies among primary tumors and metastases in patients with melanoma J. Clin. Oncol. 30 2012 2522 2529
11. J.A. Curtin, J. Fridlyand, T. Kageshita, H.N. Patel, K.J. Busam, H. Kutzner, and et al. Distinct sets of genetic alterations in melanoma N. Engl. J. Med. 353 2005 2135 2147
12. J.A. Curtin, M.S. Stark, D. Pinkel, N.K. Hayward, and B.C. Bastian PI3-kinase subunits are infrequent somatic targets in melanoma J. Invest. Dermatol. 126 2006 1660 1663
13. H. Davies, G.R. Bignell, C. Cox, P. Stephens, S. Edkins, S. Clegg, and et al. Mutations of the BRAF gene in human cancer Nature 417 2002 949 954
14. M.M. Deuker, V. Marsh Durban, W.A. Phillips, and M. McMahon PI3′-kinase inhibition forestalls the onset of MEK1/2 inhibitor resistance in BRAF-mutated melanoma Cancer Discov. 5 2015 143 153
15. B. Devitt, W. Liu, R. Salemi, R. Wolfe, J. Kelly, C.Y. Tzen, and et al. Clinical outcome and pathological features associated with NRAS mutation in cutaneous melanoma Pigment Cell Melanoma Res. 24 2011 666 672
16. N. Dhanasekaran, and E. Premkumar Reddy Signaling by dual specificity kinases Oncogene 17 1998 1447 1455
17. D. Dias-Santagata, Y. Su, and M.P. Hoang Immunohistochemical detection of NRASQ61R mutation in diverse tumor types Am. J. Clin. Pathol. 145 2016 29 34
18. Q. Dong, D.R. Dougan, X. Gong, P. Halkowycz, B. Jin, T. Kanouni, and et al. Discovery of TAK-733, a potent and selective MEK allosteric site inhibitor for the treatment of cancer Bioorg. Med. Chem. Lett. 21 2011 2135 2139
19. J. Downward Targeting RAS signalling pathways in cancer therapy Nat. Rev. Cancer 3 2003 11 22
20. J.A. Ellerhorst, V.R. Greene, S. Ekmekcioglu, C.L. Warneke, M.M. Johnson, C.P. Cooke, and et al. Clinical correlates of NRAS and BRAF mutations in primary human melanoma Clin. Cancer Res. 17 2011 229 235
21. G.S. Falchook, K.D. Lewis, J.R. Infante, M.S. Gordon, N.J. Vogelzang, D.J. DeMarini, and et al. Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: A phase 1 dose-escalation trial Lancet Oncol. 13 2012 782 789
22. I.V. Fedorenko, B. Fang, A.C. Munko, G.T. Gibney, J.M. Koomen, and K.S. Smalley Phosphoproteomic analysis of basal and therapy-induced adaptive signaling networks in BRAF and NRAS mutant melanoma Proteomics 15 2015 327 339
23. R.I. Feldman, J.M. Wu, M.A. Polokoff, M.J. Kochanny, H. Dinter, D. Zhu, and et al. Novel small molecule inhibitors of 3-phosphoinositide-dependent kinase-1 J. Biol. Chem. 280 2005 19867 19874
24. Y. Feng, P.V. LoGrasso, O. Defert, and R. Li Rho kinase (ROCK) inhibitors and their therapeutic potential J. Med. Chem. 2015 (Epub ahead of print)
25. I. Ferby, M. Reschke, O. Kudlacek, P. Knyazev, G. Pante, K. Amann, and et al. Mig6 is a negative regulator of EGF receptor-mediated skin morphogenesis and tumor formation Nat. Med. 12 2006 568 573
26. R.S. Finn, M.M. Javle, and B.R. Tan A phase 1 study of MEK inhibitor MEK162 (ARRY-438162) in patients with biliary tract cancer ASCO Gastrointestinal Cancers Symposium 2012 (abstr 220)
27. K.T. Flaherty, J.R. Infante, A. Daud, R. Gonzalez, R.F. Kefford, J. Sosman, and et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations N. Engl. J. Med. 367 2012 1694 1703
28. K.T. Flaherty, C. Robert, P. Hersey, P. Nathan, C. Garbe, M. Milhem, and et al. Improved survival with MEK inhibition in BRAF-mutated melanoma N. Engl. J. Med. 367 2012 107 114
29. B.B. Friday, and A.A. Adjei Advances in targeting the Ras/Raf/MEK/Erk mitogen-activated protein kinase cascade with MEK inhibitors for cancer therapy Clin. Cancer Res. 14 2008 342 346
30. A.G. Gilmartin, M.R. Bleam, A. Groy, K.G. Moss, E.A. Minthorn, S.G. Kulkarni, and 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 2011 989 1000
31. Y.N. Gopal, W. Deng, S.E. Woodman, K. Komurov, P. Ram, P.D. Smith, and et al. Basal and treatment-induced activation of AKT mediates resistance to cell death by AZD6244 (ARRY-142886) in braf-mutant human cutaneous melanoma cells Cancer Res. 70 2010 8736 8747
32. A. Goutopoulos, B.C. Askew, D. Bankston, A. Clark, M. Dhanabal, R. Dong, and et al. AS703026: A novel allosteric MEK inhibitor. AACR annual meeting AACR Annual Meeting 2009 (abstr 4776)
33. K.K. Grindstaff, C. Yeaman, N. Anandasabapathy, S.C. Hsu, E. Rodriguez-Boulan, R.H. Scheller, and et al. Sec6/8 complex is recruited to cell-cell contacts and specifies transport vesicle delivery to the basal-lateral membrane in epithelial cells Cell 93 1998 731 740
34. A. Gromley, C. Yeaman, J. Rosa, S. Redick, C.T. Chen, S. Mirabelle, and et al. Centriolin anchoring of exocyst and SNARE complexes at the midbody is required for secretory-vesicle-mediated abscission Cell 123 2005 75 87
35. A. Gupta, S. Love, A. Schuh, M. Shanyinde, J.M. Larkin, R. Plummer, and et al. DOC-MEK: A double blind randomized phase 2 trial of docetaxel with or without selumetinib in wild-type BRAF advanced melanoma Ann. Oncol. 25 2014 968 974
36. P.O. Hackel, M. Gishizky, and A. Ullrich Mig-6 is a negative regulator of the epidermal growth factor receptor signal Biol. Chem. 382 2001 1649 1662
37. S.K. Hanks, and A.M. Quinn Protein kinase catalytic domain sequence database: Identification of conserved features of primary structure and classification of family members Methods Enzymol. 200 1991 38 62
38. G. Hatzivassiliou, J.R. Haling, H. Chen, K. Song, S. Price, R. Heald, and et al. Mechanism of MEK inhibition determines efficacy in mutant KRAS- versus BRAF-driven cancers Nature 501 2013 232 236
39. G. Hatzivassiliou, K. Song, I. Yen, B.J. Brandhuber, D.J. Anderson, R. Alvarado, and et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth Nature 464 2010 431 435
40. S.J. Heidorn, C. Milagre, S. Whittaker, A. Nourry, I. Niculescu-Duvas, N. Dhomen, and et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF Cell 140 2010 209 221
41. J.R. Henry, M.D. Kaufman, S.B. Peng, Y.M. Ahn, T.M. Caldwell, L. Vogeti, and et al. Discovery of 1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino) pyrido[2,3-d]pyrimidin-6-yl) phenyl) urea (LY3009120) as a pan-RAF inhibitor with minimal paradoxical activation and activity against BRAF or RAS mutant tumor cells J. Med. Chem. 58 2015 4165 4179
42. J.A. Jakob, R.L. Bassett Jr., C.S. Ng, J.L. Curry, R.W. Joseph, G.C. Alvarado, and et al. NRAS mutation status is an independent prognostic factor in metastatic melanoma Cancer 118 2012 4014 4023
43. A. Jalili, A. Moser, M. Pashenkov, C. Wagner, G. Pathria, V. Borgdorff, and et al. Polo-like kinase 1 is a potential therapeutic target in human melanoma J. Invest. Dermatol. 131 2011 1886 1895
44. A. Jemal, E.P. Simard, C. Dorell, A.M. Noone, L.E. Markowitz, B. Kohler, and et al. Annual report to the nation on the status of cancer, 1975-2009, featuring the burden and trends in human papillomavirus(HPV)-associated cancers and HPV vaccination coverage levels J. Natl. Cancer Inst. 105 2013 175 201
45. D.B. Johnson, C.M. Lovly, M. Flavin, K.S. Panageas, G.D. Ayers, Z. Zhao, and et al. Impact of NRAS mutations for patients with advanced melanoma treated with immune therapies Cancer Immunol. Res. 3 2015 288 295
46. F.M. Kaplan, Y. Shao, M.M. Mayberry, and A.E. Aplin Hyperactivation of MEK-ERK1/2 signaling and resistance to apoptosis induced by the oncogenic B-RAF inhibitor PLX4720, in mutant N-RAS melanoma cells Oncogene 30 2011 366 371
47. J.M. Kirkwood, L. Bastholt, C. Robert, J. Sosman, J. Larkin, P. Hersey, and 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 2012 555 567
48. L.N. Kwong, J.C. Costello, H. Liu, S. Jiang, T.L. Helms, A.E. Langsdorf, and et al. Oncogenic NRAS signaling differentially regulates survival and proliferation in melanoma Nat. Med. 18 2012 1503 1510
49. C. Lebbe, T. Lesimple, E. Raymond, and et al. Pimasertib (MSCMSC1936369/AS703026), a selective oral MEK1/2 inhibitor, shows clinical activity in cutaneous and uveal metastatic melanoma in the phase I program European Association of Dermato-Oncology (EADO) Congress 2012 (abstr C06)
50. J.H. Lee, J.W. Choi, and Y.S. Kim Frequencies of BRAF and NRAS mutations are different in histological types and sites of origin of cutaneous melanoma: A meta-analysis Br. J. Dermatol. 164 2011 776 784
51. C.C. Lin, W.C. Su, C.J. Yen, C.H. Hsu, W.P. Su, K.H. Yeh, and et al. A phase I study of two dosing schedules of volasertib (BI 6727), an intravenous polo-like kinase inhibitor, in patients with advanced solid malignancies Br. J. Cancer 110 2014 2434 2440
52. P. Lito, M. Solomon, L.S. Li, R. Hansen, and N. Rosen Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism Science 2016 (Epub ahead of print)
53. P.M. LoRusso, S.S. Krishnamurthi, J.J. Rinehart, L.M. Nabell, L. Malburg, P.B. Chapman, and 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 2010 1924 1937
54. K. Mahajan, and N.P. Mahajan PI3K-independent AKT activation in cancers: A treasure trove for novel therapeutics J. Cell. Physiol. 227 2012 3178 3184
55. M. Malumbres, and M. Barbacid RAS oncogenes: The first 30 years Nat. Rev. Cancer 3 2003 459 465
56. M. Martinez-Garcia, U. Banerji, J. Albanell, R. Bahleda, S. Dolly, F. Kraeber-Bodere, and 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 2012 4806 4819
57. L.N. Micel, J.J. Tentler, A.C. Tan, H.M. Selby, K.L. Brunkow, K.M. Robertson, and et al. Antitumor activity of the MEK inhibitor TAK-733 against melanoma cell lines and patient-derived tumor explants Mol. Cancer Ther. 14 2015 317 325
58. C. Milagre, N. Dhomen, F.C. Geyer, R. Hayward, M. Lambros, J.S. Reis-Filho, and et al. A mouse model of melanoma driven by oncogenic KRAS Cancer Res. 70 2010 5549 5557
59. P.J. Mishra, L. Ha, J. Rieker, E.V. Sviderskaya, D.C. Bennett, M.D. Oberst, and et al. Dissection of RAS downstream pathways in melanomagenesis: A role for ral in transformation Oncogene 29 2010 2449 2456
60. E.J. Morris, S. Jha, C.R. Restaino, P. Dayananth, H. Zhu, A. Cooper, and et al. Discovery of a novel ERK inhibitor with activity in models of acquired resistance to BRAF and MEK inhibitors Cancer Discov. 3 2013 742 750
61. S. Moskalenko, D.O. Henry, C. Rosse, G. Mirey, J.H. Camonis, and M.A. White The exocyst is a ral effector complex Nat. Cell Biol. 4 2002 66 72
62. A. Nakamura, T. Arita, S. Tsuchiya, J. Donelan, J. Chouitar, E. Carideo, and et al. Antitumor activity of the selective pan-RAF inhibitor TAK-632 in BRAF inhibitor-resistant melanoma Cancer Res. 73 2013 7043 7055
63. J.M. Ostrem, U. Peters, M.L. Sos, J.A. Wells, and K.M. Shokat K-ras(G12C) inhibitors allosterically control GTP affinity and effector interactions Nature 503 2013 548 551
64. S.P. Patel, K.B. Kim, N.E. Papadopoulos, W.J. Hwu, P. Hwu, V.G. Prieto, and et al. A phase II study of gefitinib in patients with metastatic melanoma Melanoma Res. 21 2011 357 363
65. S.B. Peng, J.R. Henry, M.D. Kaufman, W.P. Lu, B.D. Smith, S. Vogeti, and et al. Inhibition of RAF isoforms and active dimers by LY3009120 leads to anti-tumor activities in RAS or BRAF mutant cancers Cancer Cell 28 2015 384 398
66. C. Posch, B.D. Cholewa, I. Vujic, M. Sanlorenzo, J. Ma, S.T. Kim, and et al. Combined inhibition of MEK and Plk1 has synergistic antitumor activity in NRAS mutant melanoma J. Invest. Dermatol. 135 2015 2475 2483
67. C. Posch, H. Moslehi, L. Feeney, G.A. Green, A. Ebaee, V. Feichtenschlager, and et al. Combined targeting of MEK and PI3 K/mTOR effector pathways is necessary to effectively inhibit NRAS mutant melanoma in vitro and in vivo Proc. Natl. Acad. Sci. U. S. A. 110 2013 4015 4020
68. P.I. Poulikakos, C. Zhang, G. Bollag, K.M. Shokat, and N. Rosen RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF Nature 464 2010 427 430
69. V.W. Rebecca, G.M. Alicea, K.H. Paraiso, H. Lawrence, G.T. Gibney, and K.S. Smalley Vertical inhibition of the MAPK pathway enhances therapeutic responses in NRAS-mutant melanoma Pigment Cell Melanoma Res. 27 2014 1154 1158
70. J. Rinehart, A.A. Adjei, P.M. Lorusso, D. Waterhouse, J.R. Hecht, R.B. Natale, and 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 2004 4456 4462
71. P.J. Roberts, J.E. Usary, D.B. Darr, P.M. Dillon, A.D. Pfefferle, M.C. Whittle, and et al. Combined PI3 K/mTOR and MEK inhibition provides broad antitumor activity in faithful murine cancer models Clin. Cancer Res. 18 2012 5290 5303
72. U. Rodeck, K. Melber, R. Kath, H.D. Menssen, M. Varello, B. Atkinson, and et al. Constitutive expression of multiple growth factor genes by melanoma cells but not normal melanocytes J. Invest. Dermatol. 97 1991 20 26
73. K. Scheffzek, M.R. Ahmadian, W. Kabsch, L. Wiesmuller, A. Lautwein, F. Schmitz, and et al. The ras-RasGAP complex: Structural basis for GTPase activation and its loss in oncogenic ras mutants Science 277 1997 333 339
74. A.J. Scheidig, C. Burmester, and R.S. Goody The pre-hydrolysis state of p21(ras) in complex with GTP: New insights into the role of water molecules in the GTP hydrolysis reaction of ras-like proteins Structure 7 1999 1311 1324
75. N. Schicher, V. Paulitschke, A. Swoboda, R. Kunstfeld, R. Loewe, P. Pilarski, and et al. Erlotinib and bevacizumab have synergistic activity against melanoma Clin. Cancer Res. 15 2009 3495 3502
76. J.A. Sosman, M. Kittaneh, P.J.K. Martijn, M.A. Postow, G. Schwartz, C. Franklin, and et al. A phase 1b/2 study of LEE011 in combination with binimetinib (MEK162) in patients with NRAS-mutant melanoma: Early encouraging clinical activity J. Clin. Oncol. 32 2014 5s (abstr 9009)
77. K.S. Spiczka, and C. Yeaman Ral-regulated interaction between Sec5 and paxillin targets exocyst to focal complexes during cell migration J. Cell Sci. 121 2008 2880 2891
78. J.M. Stahl, A. Sharma, M. Cheung, M. Zimmerman, J.Q. Cheng, M.W. Bosenberg, and et al. Deregulated Akt3 activity promotes development of malignant melanoma Cancer Res. 64 2004 7002 7010
79. C.A. Street, and B.A. Bryan Rho kinase proteins-pleiotropic modulators of cell survival and apoptosis Anticancer Res. 31 2011 3645 3657
80. J. Thumar, D. Shahbazian, S.A. Aziz, L.B. Jilaveanu, and H.M. Kluger MEK targeting in N-RAS mutated metastatic melanoma Mol. Cancer 13 45 2014 4598-13-45
81. C.J. Vogel, M.A. Smit, G. Maddalo, P.A. Possik, R.W. Sparidans, S.H. van der Burg, and et al. Cooperative induction of apoptosis in NRAS mutant melanoma by inhibition of MEK and ROCK Pigment Cell Melanoma Res. 28 2015 307 317
82. E. von Euw, M. Atefi, N. Attar, C. Chu, S. Zachariah, B.L. Burgess, and et al. Antitumor effects of the investigational selective MEK inhibitor TAK733 against cutaneous and uveal melanoma cell lines Mol. Cancer 11 2012 22
83. H.L. Vu, S. Rosenbaum, C. Capparelli, T.J. Purwin, M.A. Davies, A.C. Berger, and et al. MIG6 is MEK-regulated and affects EGF-induced migration in mutant NRAS melanoma J. Invest. Dermatol. 136 2016 453 463
84. H.L. Vu, and A.E. Aplin Targeting TBK1 inhibits migration and resistance to MEK inhibitors in mutant NRAS melanoma Mol. Cancer Res. 12 2014 1509 1519
85. M. Wada, M. Horinaka, T. Yamazaki, N. Katoh, and T. Sakai The dual RAF/MEK inhibitor CH5126766/RO5126766 may be a potential therapy for RAS-mutated tumor cells PLoS One 9 2014 e113217
86. T. Yamaguchi, R. Kakefuda, N. Tajima, Y. Sowa, and T. Sakai Antitumor activities of JTP-74057 (GSK1120212) a novel MEK1/2 inhibitor, on colorectal cancer cell lines in vitro and in vivo Int. J. Oncol. 39 2011 23 31
87. T.C. Yeh, V. Marsh, B.A. Bernat, J. Ballard, H. Colwell, R.J. Evans, and et al. Biological characterization of ARRY-142886 (AZD6244), a potent, highly selective mitogen-activated protein kinase kinase 1/2 inhibitor Clin. Cancer Res. 13 2007 1576 1583
88. T. Yoshida, J. Kakegawa, T. Yamaguchi, Y. Hantani, N. Okajima, T. Sakai, and et al. Identification and characterization of a novel chemotype MEK inhibitor able to alter the phosphorylation state of MEK1/2 Oncotarget 3 2012 1533 1545
89. L. Zimmer, F. Barlesi, M. Martinez-Garcia, V. Dieras, J.H. Schellens, J.P. Spano, and 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 2014 4251 4261
90. P.A. Zipfel, D.C. Brady, D.F. Kashatus, B.D. Ancrile, D.S. Tyler, and C.M. Counter Ral activation promotes melanomagenesis Oncogene 29 2010 4859 4864