Ras, raf, and MAP kinase in melanoma

Advances in Anatomic Pathology

Volumn 20, Issue 4, 2013, Pages 217-226

  Solus, Jason F ^a   Kraft, Stefan ^a  

^a MASSACHUSETTS GENERAL HOSPITAL   (United States)

Author keywords

Melanoma; Mitogen activated protein kinase (MAPK); Molecular pathology; Raf; Ras

Indexed keywords

B RAF KINASE; CYCLIN DEPENDENT KINASE INHIBITOR 2A; DABRAFENIB; GUANINE NUCLEOTIDE BINDING PROTEIN Q POLYPEPTIDE; MITOGEN ACTIVATED PROTEIN KINASE; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PROTEIN; PROTEIN KINASE B; PROTEIN P53; RAF PROTEIN; RAS PROTEIN; TRAMETINIB; UNCLASSIFIED DRUG; VEMURAFENIB;

APOPTOSIS; CANCER PROGNOSIS; CELL DIFFERENTIATION; CELL PROLIFERATION; CELL SURVIVAL; GENE MUTATION; GENOTYPE; HISTOPATHOLOGY; HUMAN; MELANOMA; MONOTHERAPY; ONCOGENE N RAS; PRIORITY JOURNAL; PROGRESSION FREE SURVIVAL; REVIEW; SIGNAL TRANSDUCTION;

DNA MUTATIONAL ANALYSIS; GENETIC PREDISPOSITION TO DISEASE; HUMANS; INDIVIDUALIZED MEDICINE; MELANOMA; MITOGEN-ACTIVATED PROTEIN KINASES; MUTATION; PHENOTYPE; PREDICTIVE VALUE OF TESTS; PROGNOSIS; RAF KINASES; RAS PROTEINS; SIGNAL TRANSDUCTION; SKIN NEOPLASMS; TUMOR MARKERS, BIOLOGICAL;

EID: 84880143289     PISSN: 10724109     EISSN: 15334031     Source Type: Journal    
DOI: 10.1097/PAP.0b013e3182976c94     Document Type: Review

References (146)

1. Busca R, Abbe P, Mantoux F, et al. Ras mediates the cAMPdependent activation of extracellular signal-regulated kinases (ERKs) in melanocytes. EMBO J. 2000;19:2900-2910. (Pubitemid 30386762)
2. Sullivan RJ, Flaherty K. MAP kinase signaling and inhibition in melanoma. Oncogene. 2013;32:2373-2379.
3. Beeram M, Patnaik A, Rowinsky EK. Raf: a strategic target for therapeutic development against cancer. J Clin Oncol. 2005;23:6771-6790. (Pubitemid 46194105)
4. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949-954. (Pubitemid 34716871)
5. Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med. 2005;353: 2135-2147. (Pubitemid 41653105)
6. Goel VK, Lazar AJ, Warneke CL, et al. Examination of mutations in BRAF, NRAS, and PTEN in primary cutaneous melanoma. J Invest Dermatol. 2006;126:154-160. (Pubitemid 43336107)
7. Fedorenko IV, Gibney GT, Smalley KS. NRAS mutant melanoma: Biological behavior and future strategies for therapeutic management. Oncogene. 2012. [Epub ahead of print].
8. Omholt K, Platz A, Kanter L, et al. NRAS and BRAF mutations arise early during melanoma pathogenesis and are preserved throughout tumor progression. Clin Cancer Res. 2003;9:6483-6488. (Pubitemid 38031837)
9. Tsao H, Chin L, Garraway LA, et al. Melanoma: From mutations to medicine. Genes Dev. 2012;26:1131-1155.
10. Maldonado JL, Fridlyand J, Patel H, et al. Determinants of BRAF mutations in primary melanomas. J Natl Cancer Inst. 2003;95:1878-1890.
11. Ko JM, Fisher DE. A new era: melanoma genetics and therapeutics. J Pathol. 2011;223:241-250.
12. Hocker T, Tsao H. Ultraviolet radiation and melanoma: a systematic review and analysis of reported sequence variants. Hum Mutat. 2007;28:578-588. (Pubitemid 46744288)
13. Pollock PM, Harper UL, Hansen KS, et al. High frequency of BRAF mutations in nevi. Nat Genet. 2003;33:19-20. (Pubitemid 36068675)
14. Saldanha G, Purnell D, Fletcher A, et al. High BRAF mutation frequency does not characterize all melanocytic tumor types. Int J Cancer. 2004;111:705-710. (Pubitemid 39062892)
15. Hussussian CJ, Struewing JP, Goldstein AM, et al. Germline p16 mutations in familial melanoma. Nat Genet. 1994;8: 15-21. (Pubitemid 24274055)
16. Keller-Melchior R, Schmidt R, Piepkorn M. Expression of the tumor suppressor gene product p16INK4 in benign and malignant melanocytic lesions. J Invest Dermatol. 1998; 110:932-938. (Pubitemid 28237700)
17. Michaloglou C, Vredeveld LC, Soengas MS, et al. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature. 2005;436:720-724. (Pubitemid 41117276)
18. Radhi JM. Malignant melanoma arising from nevi, p53, p16, and bcl-2: Expression in benign versus malignant components. J Cutan Med Surg. 1999;3:293-297. (Pubitemid 29467298)
19. Dhomen N, Reis-Filho JS, da Rocha Dias S, et al. Oncogenic Braf induces melanocyte senescence and melanoma in mice. Cancer Cell. 2009;15:294-303.
20. Pollock PM, Walker GJ, Glendening JM, et al. PTEN inactivation is rare in melanoma tumours but occurs frequently in melanoma cell lines. Melanoma Res. 2002;12:565-575. (Pubitemid 36042743)
21. Tsao H, Zhang X, Benoit E, et al. Identification of PTEN/ MMAC1 alterations in uncultured melanomas and melanoma cell lines. Oncogene. 1998;16:3397-3402. (Pubitemid 28349682)
22. Mikhail M, Velazquez E, Shapiro R, et al. PTEN expression in melanoma: Relationship with patient survival, bcl-2 expression, and proliferation. Clin Cancer Res. 2005;11: 5153-5157. (Pubitemid 41003700)
23. Lin WM, Baker AC, Beroukhim R, et al. Modeling genomic diversity and tumor dependency in malignant melanoma. Cancer Res. 2008;68:664-673. (Pubitemid 351206741)
24. Hodis E, Watson IR, Kryukov GV, et al. A landscape of driver mutations in melanoma. Cell. 2012;150:251-263.
25. Tsao H, Goel V, Wu H, et al. Genetic interaction between NRAS and BRAF mutations and PTEN/MMAC1 inactivation in melanoma. J Invest Dermatol. 2004;122:337-341. (Pubitemid 38281053)
26. Dankort D, Curley DP, Cartlidge RA, et al. Braf(V600E) cooperates with Pten loss to induce metastatic melanoma. Nat Genet. 2009;41:544-552.
27. Vredeveld LC, Possik PA, Smit MA, et al. Abrogation of BRAFV600E-induced senescence by PI3K pathway activation contributes to melanomagenesis. Genes Dev. 2012;26: 1055-1069.
28. Patton EE, Widlund HR, Kutok JL, et al. BRAF mutations are sufficient to promote nevi formation and cooperate with p53 in the genesis of melanoma. Curr Biol. 2005;15:249-254. (Pubitemid 40205706)
29. Chudnovsky Y, Adams AE, Robbins PB, et al. Use of human tissue to assess the oncogenic activity of melanoma-associated mutations. Nat Genet. 2005;37:745-749. (Pubitemid 41754892)
30. Chin L. The genetics of malignant melanoma: lessons from mouse and man. Nat Rev Cancer. 2003;3:559-570. (Pubitemid 37328828)
31. Gembarska A, Luciani F, Fedele C, et al. MDM4 is a key therapeutic target in cutaneous melanoma. Nat Med. 2012; 18:1239-1247.
32. Garraway LA, Widlund HR, Rubin MA, et al. Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. Nature. 2005; 436:117-122. (Pubitemid 40966196)
33. van Elsas A, Zerp SF, van der Flier S, et al. Relevance of ultraviolet-induced N-ras oncogene point mutations in development of primary human cutaneous melanoma. Am J Pathol. 1996;149:883-893. (Pubitemid 26334172)
34. Reifenberger J, Knobbe CB, Sterzinger AA, et al. Frequent alterations of Ras signaling pathway genes in sporadic malignant melanomas. Int J Cancer. 2004;109:377-384. (Pubitemid 38252766)
35. Jafari M, Papp T, Kirchner S, et al. Analysis of Ras mutations in human melanocytic lesions: activation of the Ras gene seems to be associated with the nodular type of human malignant melanoma. J Cancer Res Clin Oncol. 1995;121:23-30.
36. Edlundh-Rose E, Egyhazi S, Omholt K, et al. NRAS and BRAF mutations in melanoma tumours in relation to clinical characteristics: a study based on mutation screening by pyrosequencing. Melanoma Res. 2006;16:471-478. (Pubitemid 44934704)
37. Carr J, Mackie RM. Point mutations in the N-ras oncogene in malignant melanoma and congenital naevi. Br J Dermatol. 1994;131:72-77. (Pubitemid 24234291)
38. Dumaz N, Hayward R, Martin J, et al. In melanoma, RAS mutations are accompanied by switching signaling from BRAF to CRAF and disrupted cyclic AMP signaling. Cancer Res. 2006;66:9483-9491. (Pubitemid 44623646)
39. Bos JL. Ras oncogenes in human cancer: a review. Cancer Res. 1989;49:4682-4689. (Pubitemid 19213607)
40. Li A, Ma Y, Jin M, et al. Activated mutant NRas(Q61K) drives aberrant melanocyte signaling, survival, and invasiveness via a Rac1-dependent mechanism. J Invest Dermatol. 2012;132:2610-2621.
41. Demunter A, Stas M, Degreef H, et al. Analysis of N- and Kras mutations in the distinctive tumor progression phases of melanoma. J Invest Dermatol. 2001;117:1483-1489. (Pubitemid 34032777)
42. Omholt K, Karsberg S, Platz A, et al. Screening of N-ras codon 61 mutations in paired primary and metastatic cutaneous melanomas: mutations occur early and persist throughout tumor progression. Clin Cancer Res. 2002;8:3468-3474. (Pubitemid 35340723)
43. Bauer J, Curtin JA, Pinkel D, et al. Congenital melanocytic nevi frequently harbor NRAS mutations but no BRAF mutations. J Invest Dermatol. 2007;127:179-182. (Pubitemid 46005676)
44. Chin L, Pomerantz J, Polsky D, et al. Cooperative effects of INK4a and ras in melanoma susceptibility in vivo. Genes Dev. 1997;11:2822-2834. (Pubitemid 27481683)
45. Ackermann J, Frutschi M, Kaloulis K, et al. Metastasizing melanoma formation caused by expression of activated NRasQ61K on an INK4a-deficient background. Cancer Res. 2005;65:4005-4011. (Pubitemid 40775636)
46. Bardeesy N, Bastian BC, Hezel A, et al. Dual inactivation of RB and p53 pathways in RAS-induced melanomas. Mol Cell Biol. 2001;21:2144-2153. (Pubitemid 32479635)
47. Jonsson A, Tuominen R, Grafstrom E, et al. High frequency of p16(INK4A) promoter methylation in NRAS-mutated cutaneous melanoma. J Invest Dermatol. 2010;130:2809-2817.
48. Davies MA, Stemke-Hale K, Lin E, et al. Integrated molecular and clinical analysis of AKT activation in metastatic melanoma. Clin Cancer Res. 2009;15:7538-7546.
49. Berger MF, Hodis E, Heffernan TP, et al. Melanoma genome sequencing reveals frequent PREX2 mutations. Nature. 2012;485:502-506.
50. Krauthammer M, Kong Y, Ha BH, et al. Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma. Nat Genet. 2012;44:1006-1014.
51. Pleasance ED, Cheetham RK, Stephens PJ, et al. A comprehensive catalogue of somatic mutations from a human cancer genome. Nature. 2010;463:191-196.
52. Nikolaev SI, Rimoldi D, Iseli C, et al. Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma. Nat Genet. 2011;44:133-139.
53. Wei X, Walia V, Lin JC, et al. Exome sequencing identifies GRIN2A as frequently mutated in melanoma. Nat Genet. 2011;43:442-446.
54. Stark MS, Woods SL, Gartside MG, et al. Frequent somatic mutations in MAP3K5 and MAP3K9 in metastatic melanoma identified by exome sequencing. Nat Genet. 2011; 44:165-169.
55. Jaffe AB, Hall A. Rho GTPases: biochemistry and biology. Annu Rev Cell Dev Biol. 2005;21:247-269. (Pubitemid 41740635)
56. Vigil D, Cherfils J, Rossman KL, et al. Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy? Nat Rev Cancer. 2010;10:842-857.
57. Curtin JA, Busam K, Pinkel D, et al. Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol. 2006;24: 4340-4346. (Pubitemid 46630793)
58. Beadling C, Jacobson-Dunlop E, Hodi FS, et al. KIT gene mutations and copy number in melanoma subtypes. Clin Cancer Res. 2008;14:6821-6828.
59. Romano E, Schwartz GK, Chapman PB, et al. Treatment implications of the emerging molecular classification system for melanoma. Lancet Oncol. 2011;12:913-922.
60. Torres-Cabala CA, Wang WL, Trent J, et al. Correlation between KIT expression and KIT mutation in melanoma: a study of 173 cases with emphasis on the acral-lentiginous/ mucosal type. Mod Pathol. 2009;22:1446-1456.
61. Kong Y, Si L, Zhu Y, et al. Large-scale analysis of KIT aberrations in Chinese patients with melanoma. Clin Cancer Res. 2011;17:1684-1691.
62. Van Raamsdonk CD, Fitch KR, Fuchs H, et al. Effects of G-protein mutations on skin color. Nat Genet. 2004;36: 961-968. (Pubitemid 39167492)
63. Van Raamsdonk CD, Bezrookove V, Green G, et al. Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature. 2009;457:599-602.
64. Van Raamsdonk CD, Griewank KG, Crosby MB, et al. Mutations in GNA11 in uveal melanoma. N Engl J Med. 2010;363:2191-2199.
65. Bauer J, Buttner P, Murali R, et al. BRAF mutations in cutaneous melanoma are independently associated with age, anatomic site of the primary tumor, and the degree of solar elastosis at the primary tumor site. Pigment Cell Melanoma Res. 2011;24:345-351.
66. Liu W, Kelly JW, Trivett M, et al. Distinct clinical and pathological features are associated with the BRAF (T1799A(V600E)) mutation in primary melanoma. J Invest Dermatol. 2007;127:900-905. (Pubitemid 46434654)
67. Platz A, Egyhazi S, Ringborg U, et al. Human cutaneous melanoma; a review of NRAS and BRAF mutation frequencies in relation to histogenetic subclass and body site. Mol Oncol. 2008;1:395-405.
68. Jakob JA, Bassett RL Jr, Ng CS, et al. NRAS mutation status is an independent prognostic factor in metastatic melanoma. Cancer. 2012;118:4014-4023.
69. Ellerhorst JA, Greene VR, Ekmekcioglu S, et al. Clinical correlates of NRAS and BRAF mutations in primary human melanoma. Clin Cancer Res. 2011;17:229-235.
70. Turri-Zanoni M, Medicina D, Lombardi D, et al. Sinonasal mucosal melanoma: molecular profile and therapeutic implications from a series of 32 cases. Head Neck. 2012. [Epub ahead of print].
71. Sekine S, Nakanishi Y, Ogawa R, et al. Esophageal melanomas harbor frequent NRAS mutations unlike melanomas of other mucosal sites. Virchows Arch. 2009;454:513-517.
72. Omholt K, Grafstrom E, Kanter-Lewensohn L, et al. KIT pathway alterations in mucosal melanomas of the vulva and other sites. Clin Cancer Res. 2011;17:3933-3942.
73. Viros A, Fridlyand J, Bauer J, et al. Improving melanoma classification by integrating genetic and morphologic features. PLoS Med. 2008;5:e120.
74. Broekaert SM, Roy R, Okamoto I, et al. Genetic and morphologic features for melanoma classification. Pigment Cell Melanoma Res. 2010;23:763-770.
75. Akslen LA, Angelini S, Straume O, et al. BRAF and NRAS mutations are frequent in nodular melanoma but are not associated with tumor cell proliferation or patient survival. J Invest Dermatol. 2005;125:312-317. (Pubitemid 41648165)
76. Deichmann M, Thome M, Benner A, et al. B-raf exon 15 mutations are common in primary melanoma resection specimens but not associated with clinical outcome. Oncology. 2004;66:411-419. (Pubitemid 39194364)
77. Shinozaki M, Fujimoto A, Morton DL, et al. Incidence of BRAF oncogene mutation and clinical relevance for primary cutaneous melanomas. Clin Cancer Res. 2004;10: 1753-1757. (Pubitemid 38435567)
78. Safaee Ardekani G, Jafarnejad SM, Tan L, et al. The prognostic value of BRAF mutation in colorectal cancer and melanoma: a systematic review and meta-analysis. PLoS One. 2012;7:e47054.
79. Devitt B, Liu W, Salemi R, et al. Clinical outcome and pathological features associated with NRAS mutation in cutaneous melanoma. Pigment Cell Melanoma Res. 2011;24: 666-672.
80. Houben R, Becker JC, Kappel A, et al. Constitutive activation of the ras-raf signaling pathway in metastatic melanoma is associated with poor prognosis. J Carcinog. 2004;3:6-19.
81. Mann GJ, Pupo GM, Campain AE, et al. BRAF mutation, NRAS mutation, and the absence of an immune-related expressed gene profile predict poor outcome in patients with stage III melanoma. J Invest Dermatol. 2013;133: 509-517.
82. Moreau S, Saiag P, Aegerter P, et al. Prognostic value of BRAF(V(6)(0)(0)) mutations in melanoma patients after resection of metastatic lymph nodes. Ann Surg Oncol. 2012;19:4314-4321.
83. Whiteman DC, Pavan WJ, Bastian BC. The melanomas: a synthesis of epidemiological, clinical, histopathological, genetic, and biological aspects, supporting distinct subtypes, causal pathways, and cells of origin. Pigment Cell Melanoma Res. 2011;24:879-897.
84. Schoenewolf NL, Bull C, Belloni B, et al. Sinonasal, genital and acrolentiginous melanomas show distinct characteristics of KIT expression and mutations. Eur J Cancer. 2012; 48:1842-1852.
85. Lee JH, Choi JW, Kim YS. Frequencies of BRAF and NRAS mutations are different in histological types and sites of origin of cutaneous melanoma: a meta-analysis. Br J Dermatol. 2011;164:776-784.
86. Poynter JN, Elder JT, Fullen DR, et al. BRAF and NRAS mutations in melanoma and melanocytic nevi. Melanoma Res. 2006;16:267-273. (Pubitemid 44090170)
87. Ball NJ, Yohn JJ, Morelli JG, et al. Ras mutations in human melanoma: a marker of malignant progression. J Invest Dermatol. 1994;102:285-290.
88. Busam KJ. Desmoplastic melanoma. Clin Lab Med. 2011;31: 321-330.
89. Davison JM, Rosenbaum E, Barrett TL, et al. Absence of V599E BRAF mutations in desmoplastic melanomas. Cancer. 2005;103:788-792. (Pubitemid 40216408)
90. Kim J, Lazar AJ, Davies MA, et al. BRAF, NRAS and KIT sequencing analysis of spindle cell melanoma. J Cutan Pathol. 2012;39:821-825.
91. Miller DD, Emley A, Yang S, et al. Mixed versus pure variants of desmoplastic melanoma: a genetic and immunohistochemical appraisal. Mod Pathol. 2012;25:505-515.
92. Curry JL, Torres-Cabala CA, Tetzlaff MT, et al. Molecular platforms utilized to detect BRAF V600E mutation in melanoma. Semin Cutan Med Surg. 2012;31:267-273.
93. Sullivan RJ, Flaherty KT. BRAF in melanoma: pathogenesis, diagnosis, inhibition, and resistance. J Skin Cancer. 2011;2011:1-8.
94. Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci USA. 1977;74:5463-5467.
95. Tan YH, Liu Y, Eu KW, et al. Detection of BRAF V600E mutation by pyrosequencing. Pathology. 2008;40:295-298. (Pubitemid 351563933)
96. Lang AH, Drexel H, Geller-Rhomberg S, et al. Optimized allele-specific real-time PCR assays for the detection of common mutations in KRAS and BRAF. J Mol Diagn. 2011;13:23-28.
97. Halait H, Demartin K, Shah S, et al. Analytical performance of a real-time PCR-based assay for V600 mutations in the BRAF gene, used as the companion diagnostic test for the novel BRAF inhibitor vemurafenib in metastatic melanoma. Diagn Mol Pathol. 2012;21:1-8.
98. Ogino S, Kawasaki T, Brahmandam M, et al. Sensitive sequencing method for KRAS mutation detection by pyrosequencing. J Mol Diagn. 2005;7:413-421. (Pubitemid 41149657)
99. Ronaghi M, Shokralla S, Gharizadeh B. Pyrosequencing for discovery and analysis of DNA sequence variations. Pharmacogenomics. 2007;8:1437-1441. (Pubitemid 350162855)
100. Spittle C, Ward MR, Nathanson KL, et al. Application of a BRAF pyrosequencing assay for mutation detection and copy number analysis in malignant melanoma. J Mol Diagn. 2007;9:464-471. (Pubitemid 47434113)
101. Colomba E, Helias-Rodzewicz Z, Von Deimling A, et al. Detection of BRAF p.V600E mutations in melanomas: comparison of four methods argues for sequential use of immunohistochemistry and pyrosequencing. J Mol Diagn. 2013;15:94-100.
102. Borras E, Jurado I, Hernan I, et al. Clinical pharmacogenomic testing of KRAS, BRAF and EGFR mutations by high resolution melting analysis and ultra-deep pyrosequencing. BMC Cancer. 2011;11:406.
103. Bradic M, Costa J, Chelo IM. Genotyping with sequenom. Methods Mol Biol. 2011;772:193-210.
104. Eicher D, Merten CA. Microfluidic devices for diagnostic applications. Expert Rev Mol Diagn. 2011;11:505-519.
105. Pinzani P, Santucci C, Mancini I, et al. BRAFV600E detection in melanoma is highly improved by COLD-PCR. Clin Chim Acta. 2011;412:901-905.
106. Su Z, Ning B, Fang H, et al. Next-generation sequencing and its applications in molecular diagnostics. Expert Rev Mol Diagn. 2011;11:333-343.
107. Lovly CM, Dahlman KB, Fohn LE, et al. Routine multiplex mutational profiling of melanomas enables enrollment in genotype-driven therapeutic trials. PLoS One. 2012;7: e35309.
108. Andrulis M, Penzel R, Weichert W, et al. Application of a BRAF V600E mutation-specific antibody for the diagnosis of hairy cell leukemia. Am J Surg Pathol. 2012;32:1796-1800.
109. Capper D, Berghoff AS, Magerle M, et al. Immunohistochemical testing of BRAF V600E status in 1, 120 tumor tissue samples of patients with brain metastases. Acta Neuropathol. 2012;123:223-233.
110. Capper D, Preusser M, Habel A, et al. Assessment of BRAF V600E mutation status by immunohistochemistry with a mutation-specific monoclonal antibody. Acta Neuropathol. 2011;122:11-19.
111. Koperek O, Kornauth C, Capper D, et al. Immunohistochemical detection of the BRAF V600E-mutated protein in papillary thyroid carcinoma. Am J Surg Pathol. 2012;36: 844-850.
112. Skorokhod A, Capper D, von Deimling A, et al. Detection of BRAF V600E mutations in skin metastases of malignant melanoma by monoclonal antibody VE1. J Am Acad Dermatol. 2012;67:488-491.
113. Long GV, Wilmott JS, Capper D, et al. Immunohistochemistry is highly sensitive and specific for the detection of V600E BRAF mutation in melanoma. Am J Surg Pathol. 2013;37:61-65.
114. Busam KJ, Hedvat C, Pulitzer M, et al. Immunohistochemical analysis of BRAFV600E expression of primary and metastatic melanoma and comparison with mutation status and melanocyte differentiation antigens of metastatic lesions. Am J Surg Pathol. 2013;37:413-420.
115. Feller JK, Yang S, Mahalingam M. Immunohistochemistry with a mutation-specific monoclonal antibody as a screening tool for the BRAFV600E mutational status in primary cutaneous malignant melanoma. Mod Pathol. 2013;26:414-420.
116. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507-2516.
117. Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380:358-365.
118. Dummer R, Rozati S, Eggmann N, et al. From chemotherapy to targeted treatment. Ann Oncol. 2012;23(suppl 10):101-103.
119. Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367:107-114.
120. Kirkwood JM, Bastholt L, Robert C, et al. Phase II, openlabel, randomized trial of the MEK1/2 inhibitor selumetinib as monotherapy versus temozolomide in patients with advanced melanoma. Clin Cancer Res. 2012;18:555-567.
121. Ascierto P, Berking C, Agarwala S, et al. Efficacy and safety of oral MEK162 in patients with locally advanced and unresectable or metastatic cutaneous melanoma harboring BRAFV600 or NRAS mutations [abstract]. J Clin Oncol. 2012;30(suppl):8511.
122. Xing F, Persaud Y, Pratilas CA, et al. Concurrent loss of the PTEN and RB1 tumor suppressors attenuates RAF dependence in melanomas harboring (V600E)BRAF. Oncogene. 2012;31:446-457.
123. Villanueva J, Vultur A, Lee JT, 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. 2010;18:683-695.
124. Shi H, Moriceau G, Kong X, et al. Melanoma whole-exome sequencing identifies (V600E)B-RAF amplification-mediated acquired B-RAF inhibitor resistance. Nat Commun. 2012;3:724.
125. Tap WD, Gong KW, Dering J, et al. Pharmacodynamic characterization of the efficacy signals due to selective BRAF inhibition with PLX4032 in malignant melanoma. Neoplasia. 2010;12:637-649.
126. Nazarian R, Shi H, Wang Q, et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature. 2010;468:973-977.
127. Montagut C, Sharma SV, Shioda T, et al. Elevated CRAF as a potential mechanism of acquired resistance to BRAF inhibition in melanoma. Cancer Res. 2008;68:4853-4861.
128. Johannessen CM, Boehm JS, Kim SY, et al. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature. 2010;468:968-972.
129. Emery CM, Vijayendran KG, Zipser MC, et al. MEK1 mutations confer resistance to MEK and B-RAF inhibition. Proc Natl Acad Sci USA. 2009;106:20411-20416.
130. Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367:1694-1703.
131. Poulikakos PI, Zhang C, Bollag G, et al. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature. 2010;464:427-430.
132. Hatzivassiliou G, Song K, Yen I, et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature. 2010;464:431-435.
133. Heidorn SJ, Milagre C, Whittaker S, et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell. 2010;140:209-221.
134. Halaban R, Zhang W, Bacchiocchi A, et al. PLX4032, a selective BRAF(V600E) kinase inhibitor, activates the ERK pathway and enhances cell migration and proliferation of BRAF melanoma cells. Pigment Cell Melanoma Res. 2010;23:190-200.
135. Su F, Viros A, Milagre C, et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med. 2012;366:207-215.
136. Falchook GS, Lewis KD, Infante JR, et al. Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial. Lancet Oncol. 2012;13:782-789.
137. Kwong LN, Costello JC, Liu H, et al. Oncogenic NRAS signaling differentially regulates survival and proliferation in melanoma. Nat Med. 2012;18:1503-1510.
138. Frost MJ, Ferrao PT, Hughes TP, et al. Juxtamembrane mutant V560GKit is more sensitive to imatinib (STI571) compared with wild-type c-kit whereas the kinase domain mutant D816VKit is resistant. Mol Cancer Ther. 2002;1: 1115-1124.
139. HeinrichMC, Corless CL, Demetri GD, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 2003;21:4342-4349. (Pubitemid 46621810)
140. Mol CD, Dougan DR, Schneider TR, et al. Structural basis for the autoinhibition and STI-571 inhibition of c-kit tyrosine kinase. J Biol Chem. 2004;279:31655-31663. (Pubitemid 39037836)
141. Carvajal RD, Antonescu CR, Wolchok JD, et al. KIT as a therapeutic target in metastatic melanoma. JAMA. 2011; 305:2327-2334.
142. Minor DR, Kashani-Sabet M, Garrido M, et al. Sunitinib therapy for melanoma patients with KIT mutations. Clin Cancer Res. 2012;18:1457-1463.
143. Guo J, Si L, Kong Y, et al. Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-kit mutation or amplification. J Clin Oncol. 2011;29:2904-2909.
144. Ho AL, Musi E, Ambrosini G, et al. Impact of combined mTOR and MEK inhibition in uveal melanoma is driven by tumor genotype. PLoS One. 2012;7:e40439.
145. Khalili JS, Yu X, Wang J, et al. Combination small molecule MEK and PI3K inhibition enhances uveal melanoma cell death in a mutant GNAQ- and GNA11-dependent manner. Clin Cancer Res. 2012;18:4345-4355.
146. Wu X, Li J, Zhu M, et al. Protein kinase C inhibitor AEB071 targets ocular melanoma harboring GNAQ mutations via effects on the PKC/Erk1/2 and PKC/NF-kappaB pathways. Mol Cancer Ther. 2012;11:1905-1914.