Skip to main content
SpringerLink
Log in

Melanoma: From Tumor-Specific Mutations to a New Molecular Taxonomy and Innovative Therapeutics

  • Chapter
  • First Online:
Personalized Treatment Options in Dermatology

Abstract

Melanoma is a highly aggressive disease and the deadliest form of skin cancer. Susceptibility to melanoma can be inherited, as well as acquired by high exposure to UV rays. Early therapies had a very low response rate, and no breakthroughs in effective treatments were seen until 2011. These new therapies included small molecule inhibitors and immunotherapies. Selective B-RAF inhibitors have been shown to have a response rate of more than 50 % in patients that harbored a mutant B-RAF. Antibodies targeting CTLA-4 provided promising rates of long-term prevention of disease progression. These outcomes became possible with the learned knowledge of mutations prominent in melanoma. The ability to define a molecular signature shed light on the possible strategies and probable outcomes of different treatments. This chapter will discuss the molecular variations in melanoma, as well as the therapies being designed to exploit them.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 159.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Australian Institute of Health and Welfare & Australasian Association of Cancer Registries. Cancer in Australia: an overview, 2012. Cancer series no. 74. Cat. no. CAN 70. Canberra: AIHW; 2012.

    Google Scholar 

  2. Adjei AA, Cohen RB, Franklin W, Morris C, Wilson D, Molina JR, Hanson LJ, Gore L, Chow L, Leong S, Maloney L, Gordon G, Simmons H, Marlow A, Litwiler K, Brown S, Poch G, Kane K, Haney J, Eckhardt SG. 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. 2008;26:2139–46.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Albino AP, Vidal MJ, McNutt NS, Shea CR, Prieto VG, Nanus DM, Palmer JM, Hayward NK. Mutation and expression of the p53 gene in human malignant melanoma. Melanoma Res. 1994;4:35–45.

    Article  CAS  PubMed  Google Scholar 

  4. Ascierto PA, Schadendorf D, Berking C, Agarwala SS, van Herpen CM, Queirolo P, Blank CU, Hauschild A, Beck JT, St-Pierre A, Niazi F, Wandel S, Peters M, Zubel A, Dummer R. MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study. Lancet Oncol. 2013;14:249–56.

    Article  CAS  PubMed  Google Scholar 

  5. Balch CM, Gershenwald JE, Soong SJ, Thompson JF, Atkins MB, Byrd DR, Buzaid AC, Cochran AJ, Coit DG, Ding S, Eggermont AM, Flaherty KT, Gimotty PA, Kirkwood JM, McMasters KM, Mihm Jr MC, Morton DL, Ross MI, Sober AJ, Sondak VK. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009;27:6199–206.

    Article  PubMed Central  PubMed  Google Scholar 

  6. Bardeesy N, Kim M, Xu J, Kim RS, Shen Q, Bosenberg MW, Wong WH, Chin L. Role of epidermal growth factor receptor signaling in RAS-driven melanoma. Mol Cell Biol. 2005;25:4176–88.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Beaumont KA, Liu YY, Sturm RA. The melanocortin-1 receptor gene polymorphism and association with human skin cancer. Prog Mol Biol Transl Sci. 2009;88:85–153.

    Article  CAS  PubMed  Google Scholar 

  8. Becker B, Multhoff G, Farkas B, Wild PJ, Landthaler M, Stolz W, Vogt T. Induction of Hsp90 protein expression in malignant melanomas and melanoma metastases. Exp Dermatol. 2004;13:27–32.

    Article  CAS  PubMed  Google Scholar 

  9. Bedikian AY, Millward M, Pehamberger H, Conry R, Gore M, Trefzer U, Pavlick AC, DeConti R, Hersh EM, Hersey P, Kirkwood JM, Haluska FG. Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: the Oblimersen Melanoma Study Group. J Clin Oncol. 2006;24:4738–45.

    Article  CAS  PubMed  Google Scholar 

  10. Berger A, Quast SA, Plotz M, Kuhn NF, Trefzer U, Eberle J. RAF inhibition overcomes resistance to TRAIL-induced apoptosis in melanoma cells. J Invest Dermatol. 2014;134:430–40.

    Article  CAS  PubMed  Google Scholar 

  11. Bishop DT, Demenais F, Goldstein AM, Bergman W, Bishop JN, Bressac-de Paillerets B, Chompret A, Ghiorzo P, Gruis N, Hansson J, Harland M, Hayward N, Holland EA, Mann GJ, Mantelli M, Nancarrow D, Platz A, Tucker MA. Geographical variation in the penetrance of CDKN2A mutations for melanoma. J Natl Cancer Inst. 2002;94:894–903.

    Article  CAS  PubMed  Google Scholar 

  12. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen S, Salay TM, Alaparthy S, Grosso JF, Korman AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, Gupta A, Wigginton JM. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455–65.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Callahan MK, Postow MA, Wolchok JD. Immunomodulatory therapy for melanoma: ipilimumab and beyond. Clin Dermatol. 2013;31:191–9.

    Article  PubMed Central  PubMed  Google Scholar 

  14. Carreira S, Goodall J, Aksan I, La Rocca SA, Galibert MD, Denat L, Larue L, Goding CR. Mitf cooperates with Rb1 and activates p21Cip1 expression to regulate cell cycle progression. Nature. 2005;433:764–9.

    Article  CAS  PubMed  Google Scholar 

  15. Carvajal LA, Manfredi JJ. Another fork in the road–life or death decisions by the tumour suppressor p53. EMBO Rep. 2013;14:414–21.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Chang AE, Karnell LH, Menck HR. The National Cancer Data Base report on cutaneous and noncutaneous melanoma: a summary of 84,836 cases from the past decade. The American College of Surgeons Commission on Cancer and the American Cancer Society. Cancer. 1998;83:1664–78.

    Article  CAS  PubMed  Google Scholar 

  17. Chapman PB, Einhorn LH, Meyers ML, Saxman S, Destro AN, Panageas KS, Begg CB, Agarwala SS, Schuchter LM, Ernstoff MS, Houghton AN, Kirkwood JM. Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol. 1999;17:2745–51.

    CAS  PubMed  Google Scholar 

  18. Cho JH, Kim KM, Kwon M, Kim JH, Lee J. Nilotinib in patients with metastatic melanoma harboring KIT gene aberration. Invest New Drugs. 2012;30:2008–14.

    Article  CAS  PubMed  Google Scholar 

  19. Cipponi A, Wieers G, van Baren N, Coulie PG. Tumor-infiltrating lymphocytes: apparently good for melanoma patients. But why? Cancer Immunol Immunother. 2011;60:1153–60.

    Article  PubMed  Google Scholar 

  20. Cruz 3rd F, Rubin BP, Wilson D, Town A, Schroeder A, Haley A, Bainbridge T, Heinrich MC, Corless CL. Absence of BRAF and NRAS mutations in uveal melanoma. Cancer Res. 2003;63:5761–6.

    CAS  PubMed  Google Scholar 

  21. Curtin JA, Busam K, Pinkel D, Bastian BC. Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol. 2006;24:4340–6.

    Article  CAS  PubMed  Google Scholar 

  22. Dai DL, Martinka M, Li G. Prognostic significance of activated Akt expression in melanoma: a clinicopathologic study of 292 cases. J Clin Oncol. 2005;23:1473–82.

    Article  CAS  PubMed  Google Scholar 

  23. Dankort D, Curley DP, Cartlidge RA, Nelson B, Karnezis AN, Damsky Jr WE, You MJ, DePinho RA, McMahon M, Bosenberg M. Braf(V600E) cooperates with Pten loss to induce metastatic melanoma. Nat Genet. 2009;41:544–52.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–54.

    Article  CAS  PubMed  Google Scholar 

  25. Davies MA, Stemke-Hale K, Tellez C, Calderone TL, Deng W, Prieto VG, Lazar AJ, Gershenwald JE, Mills GB. A novel AKT3 mutation in melanoma tumours and cell lines. Br J Cancer. 2008;99:1265–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Del Vecchio M, Mortarini R, Canova S, Di Guardo L, Pimpinelli N, Sertoli MR, Bedognetti D, Queirolo P, Morosini P, Perrone T, Bajetta E, Anichini A. Bevacizumab plus fotemustine as first-line treatment in metastatic melanoma patients: clinical activity and modulation of angiogenesis and lymphangiogenesis factors. Clin Cancer Res. 2010;16:5862–72.

    Article  PubMed  CAS  Google Scholar 

  27. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, Roche PC, Lu J, Zhu G, Tamada K, Lennon VA, Celis E, Chen L. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8:793–800.

    Article  CAS  PubMed  Google Scholar 

  28. Dumaz N, Hayward R, Martin J, Ogilvie L, Hedley D, Curtin JA, Bastian BC, Springer C, Marais R. In melanoma, RAS mutations are accompanied by switching signaling from BRAF to CRAF and disrupted cyclic AMP signaling. Cancer Res. 2006;66:9483–91.

    Article  CAS  PubMed  Google Scholar 

  29. Eggermont AM, Kirkwood JM. Re-evaluating the role of dacarbazine in metastatic melanoma: what have we learned in 30 years? Eur J Cancer. 2004;40:1825–36.

    Article  CAS  PubMed  Google Scholar 

  30. Eisen T, Ahmad T, Flaherty KT, Gore M, Kaye S, Marais R, Gibbens I, Hackett S, James M, Schuchter LM, Nathanson KL, Xia C, Simantov R, Schwartz B, Poulin-Costello M, O’Dwyer PJ, Ratain MJ. Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis. Br J Cancer. 2006;95:581–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Emmett MS, Dewing D, Pritchard-Jones RO. Angiogenesis and melanoma – from basic science to clinical trials. Am J Cancer Res. 2011;1:852–68.

    PubMed Central  CAS  PubMed  Google Scholar 

  32. Emuss V, Garnett M, Mason C, Marais R. Mutations of C-RAF are rare in human cancer because C-RAF has a low basal kinase activity compared with B-RAF. Cancer Res. 2005;65:9719–26.

    Article  CAS  PubMed  Google Scholar 

  33. Ernst DS, Eisenhauer E, Wainman N, Davis M, Lohmann R, Baetz T, Belanger K, Smylie M. Phase II study of perifosine in previously untreated patients with metastatic melanoma. Invest New Drugs. 2005;23:569–75.

    Article  CAS  PubMed  Google Scholar 

  34. Fedorenko IV, Paraiso KH, Smalley KS. Acquired and intrinsic BRAF inhibitor resistance in BRAF V600E mutant melanoma. Biochem Pharmacol. 2011;82:201–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Ferlay J, SI, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon: International Agency for Research on Cancer; 2013. Available from: http://globocan.iarc.fr. Accessed on 13 Jan 2014.

  36. Fernandez-Medarde A, Santos E. Ras in cancer and developmental diseases. Genes Cancer. 2011;2:344–58.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Finn L, Markovic SN, Joseph RW. Therapy for metastatic melanoma: the past, present, and future. BMC Med. 2012;10:23.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, Hamid O, Schuchter L, Cebon J, Ibrahim N, Kudchadkar R, Burris 3rd HA, Falchook G, Algazi A, Lewis K, Long GV, Puzanov I, Lebowitz P, Singh A, Little S, Sun P, Allred A, Ouellet D, Kim KB, Patel K, Weber J. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367:1694–703.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, Demidov LV, Hassel JC, Rutkowski P, Mohr P, Dummer R, Trefzer U, Larkin JMG, Utikal J, Dreno B, Nyakas M, Middleton MR, Becker JC, Casey M, Sherman LJ, Wu FS, Ouellet D, Martin AM, Patel K, Schadendorf D, Grp MS. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367:107–14.

    Article  CAS  PubMed  Google Scholar 

  40. Furge KA, Kiewlich D, Le P, Vo MN, Faure M, Howlett AR, Lipson KE, Vande Woude GF, Webb CP. Suppression of Ras-mediated tumorigenicity and metastasis through inhibition of the Met receptor tyrosine kinase. Proc Natl Acad Sci U S A. 2001;98:10722–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Gajewski TF, Salama AK, Niedzwiecki D, Johnson J, Linette G, Bucher C, Blaskovich MA, Sebti SM, Haluska F. Phase II study of the farnesyltransferase inhibitor R115777 in advanced melanoma (CALGB 500104). J Transl Med. 2012;10:246.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Gandini S, Sera F, Cattaruzza MS, Pasquini P, Zanetti R, Masini C, Boyle P, Melchi CF. Meta-analysis of risk factors for cutaneous melanoma: III. Family history, actinic damage and phenotypic factors. Eur J Cancer. 2005;41:2040–59.

    Article  PubMed  Google Scholar 

  43. Goel VK, Lazar AJ, Warneke CL, Redston MS, Haluska FG. Examination of mutations in BRAF, NRAS, and PTEN in primary cutaneous melanoma. J Invest Dermatol. 2006;126:154–60.

    Article  CAS  PubMed  Google Scholar 

  44. Goldstein AM, Chan M, Harland M, Gillanders EM, Hayward NK, Avril MF, Azizi E, Bianchi-Scarra G, Bishop DT, Bressac-de Paillerets B, Bruno W, Calista D, Cannon Albright LA, Demenais F, Elder DE, Ghiorzo P, Gruis NA, Hansson J, Hogg D, Holland EA, Kanetsky PA, Kefford RF, Landi MT, Lang J, Leachman SA, Mackie RM, Magnusson V, Mann GJ, Niendorf K, Newton Bishop J, Palmer JM, Puig S, Puig-Butille JA, de Snoo FA, Stark M, Tsao H, Tucker MA, Whitaker L, Yakobson E. High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL. Cancer Res. 2006;66:9818–28.

    Article  CAS  PubMed  Google Scholar 

  45. Govindarajan B, Sligh JE, Vincent BJ, Li M, Canter JA, Nickoloff BJ, Rodenburg RJ, Smeitink JA, Oberley L, Zhang Y, Slingerland J, Arnold RS, Lambeth JD, Cohen C, Hilenski L, Griendling K, Martinez-Diez M, Cuezva JM, Arbiser JL. Overexpression of Akt converts radial growth melanoma to vertical growth melanoma. J Clin Invest. 2007;117:719–29.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Gray-Schopfer V, Wellbrock C, Marais R. Melanoma biology and new targeted therapy. Nature. 2007;445:851–7.

    Article  CAS  PubMed  Google Scholar 

  47. Grbovic OM, Basso AD, Sawai A, Ye Q, Friedlander P, Solit D, Rosen N. V600E B-Raf requires the Hsp90 chaperone for stability and is degraded in response to Hsp90 inhibitors. Proc Natl Acad Sci U S A. 2006;103:57–62.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Greenblatt MS, Bennett WP, Hollstein M, Harris CC. Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res. 1994;54:4855–78.

    CAS  PubMed  Google Scholar 

  49. Guo J, Si L, Kong Y, Flaherty KT, Xu X, Zhu Y, Corless CL, Li L, Li H, Sheng X, Cui C, Chi Z, Li S, Han M, Mao L, Lin X, Du N, Zhang X, Li J, Wang B, Qin S. 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;29:2904–9.

    Article  CAS  PubMed  Google Scholar 

  50. Haass NK, Sproesser K, Nguyen TK, Contractor R, Medina CA, Nathanson KL, Herlyn M, Smalley KS. The mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor AZD6244 (ARRY-142886) induces growth arrest in melanoma cells and tumor regression when combined with docetaxel. Clin Cancer Res. 2008;14:230–9.

    Article  CAS  PubMed  Google Scholar 

  51. Hainsworth JD, Infante JR, Spigel DR, Peyton JD, Thompson DS, Lane CM, Clark BL, Rubin MS, Trent DF, Burris 3rd HA. Bevacizumab and everolimus in the treatment of patients with metastatic melanoma: a phase 2 trial of the Sarah Cannon Oncology Research Consortium. Cancer. 2010;116:4122–9.

    Article  CAS  PubMed  Google Scholar 

  52. Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, Wolchok JD, Hersey P, Joseph RW, Weber JS, Dronca R, Gangadhar TC, Patnaik A, Zarour H, Joshua AM, Gergich K, Elassaiss-Schaap J, Algazi A, Mateus C, Boasberg P, Tumeh PC, Chmielowski B, Ebbinghaus SW, Li XN, Kang SP, Ribas A. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013;369:134–44.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Harbour JW, Onken MD, Roberson ED, Duan S, Cao L, Worley LA, Council ML, Matatall KA, Helms C, Bowcock AM. Frequent mutation of BAP1 in metastasizing uveal melanomas. Science. 2010;330:1410–3.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  54. Hatzivassiliou G, Song K, Yen I, Brandhuber BJ, Anderson DJ, Alvarado R, Ludlam MJ, Stokoe D, Gloor SL, Vigers G, Morales T, Aliagas I, Liu B, Sideris S, Hoeflich KP, Jaiswal BS, Seshagiri S, Koeppen H, Belvin M, Friedman LS, Malek S. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature. 2010;464:431–5.

    Article  CAS  PubMed  Google Scholar 

  55. Hill DS, Martin S, Armstrong JL, Flockhart R, Tonison JJ, Simpson DG, Birch-Machin MA, Redfern CP, Lovat PE. Combining the endoplasmic reticulum stress-inducing agents bortezomib and fenretinide as a novel therapeutic strategy for metastatic melanoma. Clin Cancer Res. 2009;15:1192–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  56. Hodi FS, Corless CL, Giobbie-Hurder A, Fletcher JA, Zhu M, Marino-Enriquez A, Friedlander P, Gonzalez R, Weber JS, Gajewski TF, O’Day SJ, Kim KB, Lawrence D, Flaherty KT, Luke JJ, Collichio FA, Ernstoff MS, Heinrich MC, Beadling C, Zukotynski KA, Yap JT, Van den Abbeele AD, Demetri GD, Fisher DE. Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun-damaged skin. J Clin Oncol. 2013;31:3182–90.

    Article  CAS  PubMed  Google Scholar 

  57. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbe C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–23.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  58. Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 2005;307:58–62.

    Article  CAS  PubMed  Google Scholar 

  59. Jansen B, Schlagbauer-Wadl H, Brown BD, Bryan RN, van Elsas A, Muller M, Wolff K, Eichler HG, Pehamberger H. bcl-2 antisense therapy chemosensitizes human melanoma in SCID mice. Nat Med. 1998;4:232–4.

    Article  CAS  PubMed  Google Scholar 

  60. Jhappan C, Noonan FP, Merlino G. Ultraviolet radiation and cutaneous malignant melanoma. Oncogene. 2003;22:3099–112.

    Article  CAS  PubMed  Google Scholar 

  61. Johannessen CM, Boehm JS, Kim SY, Thomas SR, Wardwell L, Johnson LA, Emery CM, Stransky N, Cogdill AP, Barretina J, Caponigro G, Hieronymus H, Murray RR, Salehi-Ashtiani K, Hill DE, Vidal M, Zhao JJ, Yang X, Alkan O, Kim S, Harris JL, Wilson CJ, Myer VE, Finan PM, Root DE, Roberts TM, Golub T, Flaherty KT, Dummer R, Weber BL, Sellers WR, Schlegel R, Wargo JA, Hahn WC, Garraway LA. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature. 2010;468:968–72.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  62. Kalialis LV, Drzewiecki KT, Klyver H. Spontaneous regression of metastases from melanoma: review of the literature. Melanoma Res. 2009;19:275–82.

    Article  PubMed  Google Scholar 

  63. Keuling AM, Felton KE, Parker AA, Akbari M, Andrew SE, Tron VA. RNA silencing of Mcl-1 enhances ABT-737-mediated apoptosis in melanoma: role for a caspase-8-dependent pathway. PLoS One. 2009;4:e6651.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  64. Kim KB, Sosman JA, Fruehauf JP, Linette GP, Markovic SN, McDermott DF, Weber JS, Nguyen H, Cheverton P, Chen D, Peterson AC, Carson 3rd WE, O’Day SJ. BEAM: a randomized phase II study evaluating the activity of bevacizumab in combination with carboplatin plus paclitaxel in patients with previously untreated advanced melanoma. J Clin Oncol. 2012;30:34–41.

    Article  CAS  PubMed  Google Scholar 

  65. Kirkwood JM, Bastholt L, Robert C, Sosman J, Larkin J, Hersey P, Middleton M, Cantarini M, Zazulina V, Kemsley K, Dummer R. Phase II, open-label, randomized trial of the MEK1/2 inhibitor selumetinib as monotherapy versus temozolomide in patients with advanced melanoma. Clin Cancer Res. 2012;18:555–67.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  66. Kirkwood JM, Strawderman MH, Ernstoff MS, Smith TJ, Borden EC, Blum RH. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol. 1996;14:7–17.

    CAS  PubMed  Google Scholar 

  67. Kluger HM, Dudek AZ, McCann C, Ritacco J, Southard N, Jilaveanu LB, Molinaro A, Sznol M. A phase 2 trial of dasatinib in advanced melanoma. Cancer. 2011;117:2202–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  68. Lee JT, Li L, Brafford PA, van den Eijnden M, Halloran MB, Sproesser K, Haass NK, Smalley KS, Tsai J, Bollag G, Herlyn M. PLX4032, a potent inhibitor of the B-Raf V600E oncogene, selectively inhibits V600E-positive melanomas. Pigment Cell Melanoma Res. 2010;23:820–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  69. Leiter U, Schmid RM, Kaskel P, Peter RU, Krahn G. Antiapoptotic bcl-2 and bcl-xL in advanced malignant melanoma. Arch Dermatol Res. 2000;292:225–32.

    Article  CAS  PubMed  Google Scholar 

  70. Levy C, Khaled M, Fisher DE. MITF: master regulator of melanocyte development and melanoma oncogene. Trends Mol Med. 2006;12:406–14.

    Article  CAS  PubMed  Google Scholar 

  71. Loercher AE, Tank EM, Delston RB, Harbour JW. MITF links differentiation with cell cycle arrest in melanocytes by transcriptional activation of INK4A. J Cell Biol. 2005;168:35–40.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  72. Long GV, Menzies AM, Nagrial AM, Haydu LE, Hamilton AL, Mann GJ, Hughes TM, Thompson JF, Scolyer RA, Kefford RF. Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol. 2011;29:1239–46.

    Article  PubMed  Google Scholar 

  73. Lu M, Breyssens H, Salter V, Zhong S, Hu Y, Baer C, Ratnayaka I, Sullivan A, Brown NR, Endicott J, Knapp S, Kessler BM, Middleton MR, Siebold C, Jones EY, Sviderskaya EV, Cebon J, John T, Caballero OL, Goding CR, Lu X. Restoring p53 function in human melanoma cells by inhibiting MDM2 and cyclin B1/CDK1-phosphorylated nuclear iASPP. Cancer Cell. 2013;23:618–33.

    Article  CAS  PubMed  Google Scholar 

  74. Lucas KM, Mohana-Kumaran N, Lau D, Zhang XD, Hersey P, Huang DC, Weninger W, Haass NK, Allen JD. Modulation of NOXA and MCL-1 as a strategy for sensitizing melanoma cells to the BH3-mimetic ABT-737. Clin Cancer Res. 2012;18:783–95.

    Article  CAS  PubMed  Google Scholar 

  75. Luo J, Manning BD, Cantley LC. Targeting the PI3K-Akt pathway in human cancer: rationale and promise. Cancer Cell. 2003;4:257–62.

    Article  CAS  PubMed  Google Scholar 

  76. Margolin KA, Moon J, Flaherty LE, Lao CD, Akerley 3rd WL, Othus M, Sosman JA, Kirkwood JM, Sondak VK. Randomized phase II trial of sorafenib with temsirolimus or tipifarnib in untreated metastatic melanoma (S0438). Clin Cancer Res. 2012;18:1129–37.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  77. Markovic SN, Geyer SM, Dawkins F, Sharfman W, Albertini M, Maples W, Fracasso PM, Fitch T, Lorusso P, Adjei AA, Erlichman C. A phase II study of bortezomib in the treatment of metastatic malignant melanoma. Cancer. 2005;103:2584–9.

    Article  CAS  PubMed  Google Scholar 

  78. McGill GG, Horstmann M, Widlund HR, Du J, Motyckova G, Nishimura EK, Lin YL, Ramaswamy S, Avery W, Ding HF, Jordan SA, Jackson IJ, Korsmeyer SJ, Golub TR, Fisher DE. Bcl2 regulation by the melanocyte master regulator Mitf modulates lineage survival and melanoma cell viability. Cell. 2002;109:707–18.

    Article  CAS  PubMed  Google Scholar 

  79. Meckbach D, Bauer J, Pflugfelder A, Meier F, Busch C, Eigentler TK, Capper D, von Deimling A, Mittelbronn M, Perner S, Ikenberg K, Hantschke M, Buttner P, Garbe C, Weide B. Survival according to BRAF-V600 tumor mutations – an analysis of 437 patients with primary melanoma. PLoS One. 2014;9.

    Google Scholar 

  80. Meckbach D, Keim U, Richter S, Leiter U, Eigentler TK, Bauer J, Pflugfelder A, Buttner P, Garbe C, Weide B. BRAF-V600 mutations have no prognostic impact in stage IV melanoma patients treated with monochemotherapy. PLoS One. 2014;9:e89218.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  81. Meyle KD, Guldberg P. Genetic risk factors for melanoma. Hum Genet. 2009;126:499–510.

    Article  CAS  PubMed  Google Scholar 

  82. Middleton MR, Grob JJ, Aaronson N, Fierlbeck G, Tilgen W, Seiter S, Gore M, Aamdal S, Cebon J, Coates A, Dreno B, Henz M, Schadendorf D, Kapp A, Weiss J, Fraass U, Statkevich P, Muller M, Thatcher N. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol. 2000;18:158–66.

    CAS  PubMed  Google Scholar 

  83. Miller AJ, Mihm Jr MC. Melanoma. N Engl J Med. 2006;355:51–65.

    Article  CAS  PubMed  Google Scholar 

  84. Minchinton AI, Tannock IF. Drug penetration in solid tumours. Nat Rev Cancer. 2006;6:583–92.

    Article  CAS  PubMed  Google Scholar 

  85. Minor DR, Kashani-Sabet M, Garrido M, O’Day SJ, Hamid O, Bastian BC. Sunitinib therapy for melanoma patients with KIT mutations. Clin Cancer Res. 2012;18:1457–63.

    Article  CAS  PubMed  Google Scholar 

  86. Mitra D, Luo X, Morgan A, Wang J, Hoang MP, Lo J, Guerrero CR, Lennerz JK, Mihm MC, Wargo JA, Robinson KC, Devi SP, Vanover JC, D’Orazio JA, McMahon M, Bosenberg MW, Haigis KM, Haber DA, Wang Y, Fisher DE. An ultraviolet-radiation-independent pathway to melanoma carcinogenesis in the red hair/fair skin background. Nature. 2012;491:449–53.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  87. Mohana-Kumaran N, Hill DS, Allen JD, Haass NK. Targeting the intrinsic apoptosis pathway as a strategy for melanoma therapy. Pigment Cell Melanoma Res. 2014;27:525–39.

    Google Scholar 

  88. Moloney FJ, Guitera P, Coates E, Haass NK, Ho K, Khoury R, O’Connell R, Raudonikis L, Schmid H, Mann GJ, Menzies SW. Detection of primary melanoma in individuals at extreme high risk: a prospective five-year follow up study. JAMA Dermatol. 2014;150:819–27.

    Article  PubMed  Google Scholar 

  89. Morris EJ, Jha S, Restaino CR, Dayananth P, Zhu H, Cooper A, Carr D, Deng Y, Jin W, Black S, Long B, Liu J, Dinunzio E, Windsor W, Zhang R, Zhao S, Angagaw MH, Pinheiro EM, Desai J, Xiao L, Shipps G, Hruza A, Wang J, Kelly J, Paliwal S, Gao X, Babu BS, Zhu L, Daublain P, Zhang L, Lutterbach BA, Pelletier MR, Philippar U, Siliphaivanh P, Witter D, Kirschmeier P, Bishop WR, Hicklin D, Gilliland DG, Jayaraman L, Zawel L, Fawell S, Samatar AA. Discovery of a novel ERK inhibitor with activity in models of acquired resistance to BRAF and MEK inhibitors. Cancer Discov. 2013;3:742–50.

    Article  CAS  PubMed  Google Scholar 

  90. Pavey S, Spoerri L, Haass NK, Gabrielli B. DNA repair and cell cycle checkpoint defects as drivers and therapeutic targets in melanoma. Pigment Cell Melanoma Res. 2013;26:805–16.

    Article  PubMed  Google Scholar 

  91. Pollock PM, Harper UL, Hansen KS, Yudt LM, Stark M, Robbins CM, Moses TY, Hostetter G, Wagner U, Kakareka J, Salem G, Pohida T, Heenan P, Duray P, Kallioniemi O, Hayward NK, Trent JM, Meltzer PS. High frequency of BRAF mutations in nevi. Nat Genet. 2003;33:19–20.

    Article  CAS  PubMed  Google Scholar 

  92. Poulikakos PI, Persaud Y, Janakiraman M, Kong X, Ng C, Moriceau G, Shi H, Atefi M, Titz B, Gabay MT, Salton M, Dahlman KB, Tadi M, Wargo JA, Flaherty KT, Kelley MC, Misteli T, Chapman PB, Sosman JA, Graeber TG, Ribas A, Lo RS, Rosen N, Solit DB. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature. 2011;480:387–90.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  93. Prickett TD, Agrawal NS, Wei X, Yates KE, Lin JC, Wunderlich JR, Cronin JC, Cruz P, Rosenberg SA, Samuels Y. Analysis of the tyrosine kinome in melanoma reveals recurrent mutations in ERBB4. Nat Genet. 2009;41:1127–32.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  94. Radvanyi LG, Bernatchez C, Zhang M, Fox PS, Miller P, Chacon J, Wu R, Lizee G, Mahoney S, Alvarado G, Glass M, Johnson VE, McMannis JD, Shpall E, Prieto V, Papadopoulos N, Kim K, Homsi J, Bedikian A, Hwu WJ, Patel S, Ross MI, Lee JE, Gershenwald JE, Lucci A, Royal R, Cormier JN, Davies MA, Mansaray R, Fulbright OJ, Toth C, Ramachandran R, Wardell S, Gonzalez A, Hwu P. Specific lymphocyte subsets predict response to adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma patients. Clin Cancer Res. 2012;18:6758–70.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  95. Rimoldi D, Salvi S, Lienard D, Lejeune FJ, Speiser D, Zografos L, Cerottini JC. Lack of BRAF mutations in uveal melanoma. Cancer Res. 2003;63:5712–5.

    CAS  PubMed  Google Scholar 

  96. Robert C, Dummer R, Gutzmer R, Lorigan P, Kim KB, Nyakas M, Arance A, Liszkay G, Schadendorf D, Cantarini M, Spencer S, Middleton MR. 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. 2013;14:733–40.

    Article  CAS  PubMed  Google Scholar 

  97. Robert C, Thomas L, Bondarenko I, O’Day S, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller Jr WH, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok JD. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517–26.

    Article  CAS  PubMed  Google Scholar 

  98. Rosenberg SA, Dudley ME. Adoptive cell therapy for the treatment of patients with metastatic melanoma. Curr Opin Immunol. 2009;21:233–40.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  99. Rosenberg SA, Yang JC, Topalian SL, Schwartzentruber DJ, Weber JS, Parkinson DR, Seipp CA, Einhorn JH, White DE. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA. 1994;271:907–13.

    Article  CAS  PubMed  Google Scholar 

  100. Schmittel A, Schmidt-Hieber M, Martus P, Bechrakis NE, Schuster R, Siehl JM, Foerster MH, Thiel E, Keilholz U. A randomized phase II trial of gemcitabine plus treosulfan versus treosulfan alone in patients with metastatic uveal melanoma. Ann Oncol. 2006;17:1826–9.

    Article  CAS  PubMed  Google Scholar 

  101. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63:11–30.

    Article  PubMed  Google Scholar 

  102. Smalley KS, Haass NK, Brafford PA, Lioni M, Flaherty KT, Herlyn M. Multiple signaling pathways must be targeted to overcome drug resistance in cell lines derived from melanoma metastases. Mol Cancer Ther. 2006;5:1136–44.

    Article  CAS  PubMed  Google Scholar 

  103. Soufir N, Avril MF, Chompret A, Demenais F, Bombled J, Spatz A, Stoppa-Lyonnet D, Benard J, Bressac-de Paillerets B. Prevalence of p16 and CDK4 germline mutations in 48 melanoma-prone families in France. The French Familial Melanoma Study Group. Hum Mol Genet. 1998;7:209–16.

    Article  CAS  PubMed  Google Scholar 

  104. Stahl JM, Sharma A, Cheung M, Zimmerman M, Cheng JQ, Bosenberg MW, Kester M, Sandirasegarane L, Robertson GP. Deregulated Akt3 activity promotes development of malignant melanoma. Cancer Res. 2004;64:7002–10.

    Article  CAS  PubMed  Google Scholar 

  105. Stehn JR, Haass NK, Bonello T, Desouza M, Kottyan G, Treutlein H, Zeng J, Nascimento PR, Sequeira VB, Butler TL, Allanson M, Fath T, Hill TA, McCluskey A, Schevzov G, Palmer SJ, Hardeman EC, Winlaw D, Reeve VE, Dixon I, Weninger W, Cripe TP, Gunning PW. A novel class of anticancer compounds targets the actin cytoskeleton in tumor cells. Cancer Res. 2013;73:5169–82.

    Article  CAS  PubMed  Google Scholar 

  106. Su F, Viros A, Milagre C, Trunzer K, Bollag G, Spleiss O, Reis-Filho JS, Kong X, Koya RC, Flaherty KT, Chapman PB, Kim MJ, Hayward R, Martin M, Yang H, Wang Q, Hilton H, Hang JS, Noe J, Lambros M, Geyer F, Dhomen N, Niculescu-Duvaz I, Zambon A, Niculescu-Duvaz D, Preece N, Robert L, Otte NJ, Mok S, Kee D, Ma Y, Zhang C, Habets G, Burton EA, Wong B, Nguyen H, Kockx M, Andries L, Lestini B, Nolop KB, Lee RJ, Joe AK, Troy JL, Gonzalez R, Hutson TE, Puzanov I, Chmielowski B, Springer CJ, McArthur GA, Sosman JA, Lo RS, Ribas A, Marais R. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med. 2012;366:207–15.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  107. Sullivan RJ, Flaherty K. MAP kinase signaling and inhibition in melanoma. Oncogene. 2013;32:2373–9.

    Article  CAS  PubMed  Google Scholar 

  108. Tabas I, Ron D. Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nat Cell Biol. 2011;13:184–90.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  109. Tang L, Tron VA, Reed JC, Mah KJ, Krajewska M, Li G, Zhou X, Ho VC, Trotter MJ. Expression of apoptosis regulators in cutaneous malignant melanoma. Clin Cancer Res. 1998;4:1865–71.

    CAS  PubMed  Google Scholar 

  110. Tsai J, Lee JT, Wang W, Zhang J, Cho H, Mamo S, Bremer R, Gillette S, Kong J, Haass NK, Sproesser K, Li L, Smalley KS, Fong D, Zhu YL, Marimuthu A, Nguyen H, Lam B, Liu J, Cheung I, Rice J, Suzuki Y, Luu C, Settachatgul C, Shellooe R, Cantwell J, Kim SH, Schlessinger J, Zhang KY, West BL, Powell B, Habets G, Zhang C, Ibrahim PN, Hirth P, Artis DR, Herlyn M, Bollag G. Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proc Natl Acad Sci U S A. 2008;105:3041–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  111. Valverde P, Healy E, Sikkink S, Haldane F, Thody AJ, Carothers A, Jackson IJ, Rees JL. The Asp84Glu variant of the melanocortin 1 receptor (MC1R) is associated with melanoma. Hum Mol Genet. 1996;5:1663–6.

    Article  CAS  PubMed  Google Scholar 

  112. Van Raamsdonk CD, Bezrookove V, Green G, Bauer J, Gaugler L, O’Brien JM, Simpson EM, Barsh GS, Bastian BC. Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature. 2009;457:599–602.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  113. Villanueva J, Vultur A, Herlyn M. Resistance to BRAF inhibitors: unraveling mechanisms and future treatment options. Cancer Res. 2011;71:7137–40.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  114. von Moos R, Seifert B, Simcock M, Goldinger SM, Gillessen S, Ochsenbein A, Michielin O, Cathomas R, Schlappi M, Moch H, Schraml PH, Mjhic-Probst D, Mamot C, Schonewolf N, Dummer R. First-line temozolomide combined with bevacizumab in metastatic melanoma: a multicentre phase II trial (SAKK 50/07). Ann Oncol. 2012;23:531–6.

    Article  Google Scholar 

  115. Wagle N, Emery C, Berger MF, Davis MJ, Sawyer A, Pochanard P, Kehoe SM, Johannessen CM, MacConaill LE, Hahn WC, Meyerson M, Garraway LA. Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling. J Clin Oncol. 2011;29:3085–96.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  116. Wang Q, Beaumont KA, Otte NJ, Font J, Bailey CG, van Geldermalsen M, Sharp DM, Tiffen JC, Ryan RM, Jormakka M, Haass NK, Rasko JE, Holst J. Targeting glutamine transport to suppress melanoma cell growth. Int J Cancer. 2014;135:1060–71.

    Article  CAS  PubMed  Google Scholar 

  117. Wiesner T, Obenauf AC, Murali R, Fried I, Griewank KG, Ulz P, Windpassinger C, Wackernagel W, Loy S, Wolf I, Viale A, Lash AE, Pirun M, Socci ND, Rutten A, Palmedo G, Abramson D, Offit K, Ott A, Becker JC, Cerroni L, Kutzner H, Bastian BC, Speicher MR. Germline mutations in BAP1 predispose to melanocytic tumors. Nat Genet. 2011;43:1018–21.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  118. Wilhelm SM, Carter C, Tang LY, Wilkie D, McNabola A, Rong H, Chen C, Zhang XM, Vincent P, McHugh M, Cao YC, Shujath J, Gawlak S, Eveleigh D, Rowley B, Liu L, Adnane L, Lynch M, Auclair D, Taylor I, Gedrich R, Voznesensky A, Riedl B, Post LE, Bollag G, Trail PA. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004;64:7099–109.

    Article  CAS  PubMed  Google Scholar 

  119. Willis SN, Adams JM. Life in the balance: how BH3-only proteins induce apoptosis. Curr Opin Cell Biol. 2005;17:617–25.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  120. Willmore-Payne C, Holden JA, Tripp S, Layfield LJ. Human malignant melanoma: detection of BRAF- and c-kit-activating mutations by high-resolution amplicon melting analysis. Hum Pathol. 2005;36:486–93.

    Article  CAS  PubMed  Google Scholar 

  121. Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, Gordon RA, Reed K, Burke MM, Caldwell A, Kronenberg SA, Agunwamba BU, Zhang X, Lowy I, Inzunza HD, Feely W, Horak CE, Hong Q, Korman AJ, Wigginton JM, Gupta A, Sznol M. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369:122–33.

    Article  CAS  PubMed  Google Scholar 

  122. Wroblewski D, Mijatov B, Mohana-Kumaran N, Lai F, Gallagher SJ, Haass NK, Zhang XD, Hersey P. The BH3-mimetic ABT-737 sensitizes human melanoma cells to apoptosis induced by selective BRAF inhibitors but does not reverse acquired resistance. Carcinogenesis. 2013;34:237–247.

    Google Scholar 

  123. Yang G, Rajadurai A, Tsao H. Recurrent patterns of dual RB and p53 pathway inactivation in melanoma. J Invest Dermatol. 2005;125:1242–51.

    Article  CAS  PubMed  Google Scholar 

  124. Yokoyama S, Woods SL, Boyle GM, Aoude LG, MacGregor S, Zismann V, Gartside M, Cust AE, Haq R, Harland M, Taylor JC, Duffy DL, Holohan K, Dutton-Regester K, Palmer JM, Bonazzi V, Stark MS, Symmons J, Law MH, Schmidt C, Lanagan C, O’Connor L, Holland EA, Schmid H, Maskiell JA, Jetann J, Ferguson M, Jenkins MA, Kefford RF, Giles GG, Armstrong BK, Aitken JF, Hopper JL, Whiteman DC, Pharoah PD, Easton DF, Dunning AM, Newton-Bishop JA, Montgomery GW, Martin NG, Mann GJ, Bishop DT, Tsao H, Trent JM, Fisher DE, Hayward NK, Brown KM. A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma. Nature. 2011;480:99–103.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  125. Zuo L, Weger J, Yang Q, Goldstein AM, Tucker MA, Walker GJ, Hayward N, Dracopoli NC. Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma. Nat Genet. 1996;12:97–9.

    Article  CAS  PubMed  Google Scholar 

  126. Robert L, Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Chmielowski B, Spasic M, Henry G, Ciobanu V, West AN, Carmona M, Kivork C, Seja E, Cherry G, Gutierrez AJ, Grogan TR, Mateus C, Tomasic G, Glaspy JA, Emerson RO, Robins H, Pierce RH, Elashoff DA, Robert C, Ribas A. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014;384(9948):1109–17.

    Google Scholar 

  127. Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, Chmielowski B, Spasic M, Henry G, Ciobanu V, West AN, Carmona M, Kivork C, Seja E, Cherry G, Gutierrez AJ, Grogan TR, Mateus C, Tomasic G, Glaspy JA, Emerson RO, Robins H, Pierce RH, Elashoff DA, Robert C, Ribas A. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515(7528):568–71.

    Google Scholar 

Download references

Acknowledgments

N.K.H. is a Cameron Fellow of the Melanoma and Skin Cancer Research Institute, Australia, and a Sydney Medical School Foundation Fellow. N.K.H. also acknowledges contributing grant support from the Cancer Council NSW (RG 09-08, RG 13-06), Cancer Australia/Cure Cancer Australia Foundation (570778), Cancer Institute New South Wales (08/RFG/1-27), and the National Health and Medical Research Council Australia (1003637). We would also like to thank Dr. Lucas B. Murray, The University of Queensland Medical School, and Ms. Sheena Daignault, The University of Queensland Diamantina Institute, for carefully proofreading the manuscript.

Author information

Authors and Affiliations

  1. Experimental Melanoma Therapy Laboratory, The University of Queensland Diamantina Institute, Translational Research Institute, Woolloongabba, Brisbane, QLD, 4102, Australia

    Crystal A. Tonnessen PhD & Nikolas K. Haass MD, PhD

Authors
  1. Crystal A. Tonnessen PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nikolas K. Haass MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nikolas K. Haass MD, PhD .

Editor information

Editors and Affiliations

  1. Department of Dermatology and Allergy, Center of Translational Medicine, University of Bonn, Bonn, Germany

    Thomas Bieber

  2. St. John's Institute of Dermatology, London, United Kingdom

    Frank Nestle

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Tonnessen, C.A., Haass, N.K. (2015). Melanoma: From Tumor-Specific Mutations to a New Molecular Taxonomy and Innovative Therapeutics. In: Bieber, T., Nestle, F. (eds) Personalized Treatment Options in Dermatology. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-45840-2_2

Download citation

  • DOI: https://doi.org/10.1007/978-3-662-45840-2_2

  • Published:

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-662-45839-6

  • Online ISBN: 978-3-662-45840-2

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation