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Targeted Therapies in Melanoma

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Targeted Therapies for Solid Tumors

Part of the book series: Current Clinical Pathology ((CCPATH))

Abstract

The standard approach for malignant melanoma is represented by surgical excision. In most cases, distant metastases develop. Until few years ago, the main strategies to treat metastatic melanoma were chemotherapy and cytokines with subsequent low efficacy and poor tolerability profile. In the last few years, a new biological therapy has become available for metastatic melanoma. It includes targeted therapy, such as BRAF inhibitors (vemurafenib and dabrafenib) and MEK inhibitors (trametinib), and immunotherapy, such as the monoclonal antibodies anti-CTLA-4 (ipilimumab) and anti-PD-1 (nivolumab and lambrolizumab). The different mechanisms of action of these new drugs imply a variability of outcomes achieved and tolerability profiles. Consequently, the therapeutic options for patients who are diagnosed with metastatic malignant melanoma have been radically changed.

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References

  1. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64(1):9–29.

    Google Scholar 

  2. 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(8):1664–78.

    Google Scholar 

  3. Tas F, Keskin S, Karadeniz A, Dagoglu N, Sen F, Kilic L, Yildiz I. Noncutaneous melanoma have distinct features from each other and cutaneous melanoma. Oncology. 2011;81(5–6):353–8.

    Google Scholar 

  4. Greenberg E, Nemlich Y, Markel G. MicroRNAs in cancer: lessons from Melanoma. Curr Pharm Des. 2014;20(33):5246–59.

    Article  CAS  PubMed  Google Scholar 

  5. Oba-Shinjo SM, Correa M, Ricca TI, Molognoni F, Pinhal MA, Neves IA, Marie SK, Sampaio LO, Nader HB, Chammas R, et al. Melanocyte transformation associated with substrate adhesion impediment. Neoplasia. 2006;8(3):231–41.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Jhappan C, Noonan FP, Merlino G. Ultraviolet radiation and cutaneous malignant melanoma. Oncogene. 2003;22(20):3099–12.

    Article  CAS  PubMed  Google Scholar 

  7. Bhatia S, Emdad L, Das SK, Hamed H, Dent P, Sarkar D, Fisher PB. Non-BRAF targeted therapies for melanoma: protein kinase inhibitors in Phase II clinical trials. Expert Opin Investig Drugs. 2014;23(4):489–500.

    Article  CAS  PubMed  Google Scholar 

  8. Caramuta S, Egyhazi S, Rodolfo M, Witten D, Hansson J, Larsson C, Lui WO. MicroRNA expression profiles associated with mutational status and survival in malignant melanoma. J Invest Dermatol. 2010;130(8):2062–70.

    Article  CAS  PubMed  Google Scholar 

  9. Curtin JA, Fridlyand J, Kageshita T, Patel HN, Busam KJ, Kutzner H, Cho KH, Aiba S, Brocker EB, LeBoit PE, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med. 2005;353(20):2135–47.

    Article  CAS  PubMed  Google Scholar 

  10. Pollock PM, Harper UL, Hansen KS, Yudt LM, Stark M, Robbins CM, Moses TY, Hostetter G, Wagner U, Kakareka J, et al. High frequency of BRAF mutations in nevi. Nat Genet. 2003;33(1):19–20.

    Article  CAS  PubMed  Google Scholar 

  11. Yeh I, von Deimling A, Bastian BC. Clonal BRAF mutations in melanocytic nevi and initiating role of BRAF in melanocytic neoplasia. J Natl Cancer Inst. 2013;105(12):917–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Kunz M. Oncogenes in melanoma: an update. Eur J Cell Biol. 2014;93(1–2):1–10.

    Article  CAS  PubMed  Google Scholar 

  13. Chudnovsky Y, Adams AE, Robbins PB, Lin Q, Khavari PA. Use of human tissue to assess the oncogenic activity of melanoma-associated mutations. Nat Genet. 2005;37(7):745–9

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. 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(19):7002–10.

    Article  CAS  PubMed  Google Scholar 

  15. Stahl JM, Cheung M, Sharma A, Trivedi NR, Shanmugam S, Robertson GP. Loss of PTEN promotes tumor development in malignant melanoma. Cancer Res. 2003;63(11):2881–90.

    CAS  PubMed  Google Scholar 

  16. Shull AY, Latham-Schwark A, Ramasamy P, Leskoske K, Oroian D, Birtwistle MR, Buckhaults PJ. Novel somatic mutations to PI3K pathway genes in metastatic melanoma. PLoS One. 2012;7(8):e43369.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Berger MF, Hodis E, Heffernan TP, Deribe YL, Lawrence MS, Protopopov A, Ivanova E, Watson IR, Nickerson E, Ghosh P, et al. Melanoma genome sequencing reveals frequent PREX2 mutations. Nature. 2012;485(7399):502–6.

    PubMed Central  CAS  PubMed  Google Scholar 

  18. Hodis E, Watson IR, Kryukov GV, Arold ST, Imielinski M, Theurillat JP, Nickerson E, Auclair D, Li L, Place C, et al. A landscape of driver mutations in melanoma. Cell. 2012;150(2):251–63.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Krauthammer M, Kong Y, Ha BH, Evans P, Bacchiocchi A, McCusker JP, Cheng E, Davis MJ, Goh G, Choi M, et al. Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma. Nat Genet. 2012;44(9):1006–14.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. 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(1):97–9.

    Article  CAS  PubMed  Google Scholar 

  21. Hussussian CJ, Struewing JP, Goldstein AM, Higgins PA, Ally DS, Sheahan MD, Clark WH Jr, Tucker MA, Dracopoli NC. Germline p16 mutations in familial melanoma. Nat Genet. 1994;8(1):15–21.

    Article  CAS  PubMed  Google Scholar 

  22. Fanale D, Amodeo V, Corsini LR, Rizzo S, Bazan V, Russo A. Breast cancer genome-wide association studies: there is strength in numbers. Oncogene. 2012;31(17):2121–8.

    Article  CAS  PubMed  Google Scholar 

  23. Bressac-de-Paillerets B, Avril MF, Chompret A, Demenais F. Genetic and environmental factors in cutaneous malignant melanoma. Biochimie. 2002;84(1):67–74.

    Article  CAS  PubMed  Google Scholar 

  24. Fargnoli MC, Gandini S, Peris K, Maisonneuve P, Raimondi S. MC1R variants increase melanoma risk in families with CDKN2A mutations: a meta-analysis. Eur J Cancer. 2010;46(8):1413–20.

    Article  CAS  PubMed  Google Scholar 

  25. Yokoyama S, Woods SL, Boyle GM, Aoude LG, MacGregor S, Zismann V, Gartside M, Cust AE, Haq R, Harland M, et al. A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma. Nature. 2011;480(7375):99–103.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Bertolotto C, Lesueur F, Giuliano S, Strub T, de Lichy M, Bille K, Dessen P, d’Hayer B, Mohamdi H, Remenieras A, et al. A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma. Nature. 2011;480(7375):94–8.

    Article  CAS  PubMed  Google Scholar 

  27. Sturm RA, Fox C, McClenahan P, Jagirdar K, Ibarrola-Villava M, Banan P, Abbott NC, Ribas G, Gabrielli B, Duffy DL, et al. Phenotypic characterization of nevus and tumor patterns in MITF E318K mutation carrier melanoma patients. J Invest Dermatol. 2014;134(1):141–9.

    Article  CAS  PubMed  Google Scholar 

  28. Ghiorzo P, Pastorino L, Queirolo P, Bruno W, Tibiletti MG, Nasti S, Andreotti V, Paillerets BB, Bianchi Scarra G. Prevalence of the E318K MITF germline mutation in Italian melanoma patients: associations with histological subtypes and family cancer history. Pigment Cell Melanoma Res. 2013;26(2):259–62.

    Article  CAS  PubMed  Google Scholar 

  29. Strub T, Giuliano S, Ye T, Bonet C, Keime C, Kobi D, Le Gras S, Cormont M, Ballotti R, Bertolotto C, et al. Essential role of microphthalmia transcription factor for DNA replication, mitosis and genomic stability in melanoma. Oncogene. 2011;30(20):2319–32.

    Article  CAS  PubMed  Google Scholar 

  30. Kauffmann A, Rosselli F, Lazar V, Winnepenninckx V, Mansuet-Lupo A, Dessen P, van den Oord JJ, Spatz A, Sarasin A. High expression of DNA repair pathways is associated with metastasis in melanoma patients. Oncogene. 2008;27(5):565–73.

    Article  CAS  PubMed  Google Scholar 

  31. Wei X, Walia V, Lin JC, Teer JK, Prickett TD, Gartner J, Davis S, Stemke-Hale K, Davies MA, Gershenwald JE, et al. Exome sequencing identifies GRIN2A as frequently mutated in melanoma. Nat Genet. 2011;43(5):442–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. 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(10):1127–32.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Palavalli LH, Prickett TD, Wunderlich JR, Wei X, Burrell AS, Porter-Gill P, Davis S, Wang C, Cronin JC, Agrawal NS, et al. Analysis of the matrix metalloproteinase family reveals that MMP8 is often mutated in melanoma. Nat Genet. 2009;41(5):518–20.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Bertolotto C. Melanoma: from melanocyte to genetic alterations and clinical options. Scientifica (Cairo). 2013;2013:635203.

    Google Scholar 

  35. Ghosh P, Chin L. Genetics and genomics of melanoma. Expert Rev Dermatol. 2009;4(2):131.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Jafari M, Papp T, Kirchner S, Diener U, Henschler D, Burg G, Schiffmann D. 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(1):23–30

    Article  CAS  PubMed  Google Scholar 

  37. van Elsas A, Zerp SF, van der Flier S, Kruse KM, Aarnoudse C, Hayward NK, Ruiter DJ, Schrier PI. Relevance of ultraviolet-induced N-ras oncogene point mutations in development of primary human cutaneous melanoma. Am J Pathol. 1996;149(3):883–93.

    PubMed Central  PubMed  Google Scholar 

  38. Ellerhorst JA, Greene VR, Ekmekcioglu S, Warneke CL, Johnson MM, Cooke CP, Wang LE, Prieto VG, Gershenwald JE, Wei Q, et al. Clinical correlates of NRAS and BRAF mutations in primary human melanoma. Clin Cancer Res. 2011;17(2):229–35.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Bastian BC, LeBoit PE, Pinkel D. Mutations and copy number increase of HRAS in Spitz nevi with distinctive histopathological features. Am J Pathol. 2000;157(3):967–72.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Wellbrock C, Hurlstone A. BRAF as therapeutic target in melanoma. Biochem Pharmacol. 2010;80(5):561–7.

    Article  CAS  PubMed  Google Scholar 

  41. 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(10):1239–46.

    Article  PubMed  Google Scholar 

  42. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892):949–54.

    Article  CAS  PubMed  Google Scholar 

  43. Madureira P, de Mello RA. BRAF and MEK gene rearrangements in melanoma: implications for targeted therapy. Mol Diagn Ther. 2014;18(3):285–91.

    CAS  PubMed  Google Scholar 

  44. Thomas NE. BRAF somatic mutations in malignant melanoma and melanocytic naevi. Melanoma Res. 2006;16(2):97–103.

    Article  CAS  PubMed  Google Scholar 

  45. Omholt K, Platz A, Kanter L, Ringborg U, Hansson J. NRAS and BRAF mutations arise early during melanoma pathogenesis and are preserved throughout tumor progression. Clin Cancer Res. 2003;9(17):6483–8.

    CAS  PubMed  Google Scholar 

  46. Edlundh-Rose E, Egyhazi S, Omholt K, Mansson-Brahme E, Platz A, Hansson J, Lundeberg J. NRAS and BRAF mutations in melanoma tumours in relation to clinical characteristics: a study based on mutation screening by pyrosequencing. Melanoma Res. 2006;16(6):471–8.

    Article  CAS  PubMed  Google Scholar 

  47. Platz A, Egyhazi S, Ringborg U, Hansson J. Human cutaneous melanoma; a review of NRAS and BRAF mutation frequencies in relation to histogenetic subclass and body site. Mol Oncol. 2008;1(4):395–405.

    Article  PubMed  Google Scholar 

  48. Liu J, Suresh Kumar KG, Yu D, Molton SA, McMahon M, Herlyn M, Thomas-Tikhonenko A, Fuchs SY. Oncogenic BRAF regulates beta-Trcp expression and NF-kappaB activity in human melanoma cells. Oncogene. 2007;26(13):1954–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Bhatt KV, Hu R, Spofford LS, Aplin AE. Mutant B-RAF signaling and cyclin D1 regulate Cks1/S-phase kinase-associated protein 2-mediated degradation of p27Kip1 in human melanoma cells. Oncogene. 2007;26(7):1056–66.

    Article  CAS  PubMed  Google Scholar 

  50. Caramel J, Papadogeorgakis E, Hill L, Browne GJ, Richard G, Wierinckx A, Saldanha G, Osborne J, Hutchinson P, Tse G, et al. A switch in the expression of embryonic EMT-inducers drives the development of malignant melanoma. Cancer Cell. 2013;24(4):466–80.

    Article  CAS  PubMed  Google Scholar 

  51. Sharma A, Tran MA, Liang S, Sharma AK, Amin S, Smith CD, Dong C, Robertson GP. Targeting mitogen-activated protein kinase/extracellular signal-regulated kinase kinase in the mutant (V600E) B-Raf signaling cascade effectively inhibits melanoma lung metastases. Cancer Res. 2006;66(16):8200–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  52. Shields JM, Thomas NE, Cregger M, Berger AJ, Leslie M, Torrice C, Hao H, Penland S, Arbiser J, Scott G, et al. Lack of extracellular signal-regulated kinase mitogen-activated protein kinase signaling shows a new type of melanoma. Cancer Res. 2007;67(4):1502–12.

    Article  CAS  PubMed  Google Scholar 

  53. Kortylewski M, Heinrich PC, Kauffmann ME, Bohm M, MacKiewicz A, Behrmann I. Mitogen-activated protein kinases control p27/Kip1 expression and growth of human melanoma cells. Biochem J. 2001;357(Pt 1):297–303.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  54. Huntington JT, Shields JM, Der CJ, Wyatt CA, Benbow U, Slingluff CL Jr, Brinckerhoff CE. Overexpression of collagenase 1 (MMP-1) is mediated by the ERK pathway in invasive melanoma cells: role of BRAF mutation and fibroblast growth factor signaling. J Biol Chem. 2004;279(32):33168–76.

    Article  CAS  PubMed  Google Scholar 

  55. Cole BF, Gelber RD, Kirkwood JM, Goldhirsch A, Barylak E, Borden E. Quality-of-life-adjusted survival analysis of interferon alfa-2b adjuvant treatment of high-risk resected cutaneous melanoma: an Eastern Cooperative Oncology Group Study. J Clin Oncol. 1996;14(10):2666–73.

    CAS  PubMed  Google Scholar 

  56. Romano E, Scordo M, Dusza SW, Coit DG, Chapman PB. Site and timing of first relapse in stage III melanoma patients: implications for follow-up guidelines. J Clin Oncol. 2010;28(18):3042–7.

    Article  PubMed Central  PubMed  Google Scholar 

  57. Rughani MG, Gupta A, Middleton MR. New treatment approaches in melanoma: current research and clinical prospects. Ther Adv Med Oncol. 2013;5(1):73–80.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  58. Rao NG, Yu HH, Trotti A III, Sondak VK. The role of radiation therapy in the management of cutaneous melanoma. Surg Oncol Clin N Am. 2011;20(1):115–31.

    Article  PubMed  Google Scholar 

  59. Middleton MR, Grob JJ, Aaronson N, Fierlbeck G, Tilgen W, Seiter S, Gore M, Aamdal S, Cebon J, Coates A, et al. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol. 2000;18(1):158–66.

    CAS  PubMed  Google Scholar 

  60. Tsao H, Atkins MB, Sober AJ. Management of cutaneous melanoma. N Engl J Med. 2004;351(10):998–1012.

    Article  CAS  PubMed  Google Scholar 

  61. Griewank KG, Scolyer RA, Thompson JF, Flaherty KT, Schadendorf D, Murali R. Genetic alterations and personalized medicine in melanoma: progress and future prospects. J Natl Cancer Inst. 2014;106(2):djt435.

    Article  PubMed  Google Scholar 

  62. Omholt K, Grafstrom E, Kanter-Lewensohn L, Hansson J, Ragnarsson-Olding BK. KIT pathway alterations in mucosal melanomas of the vulva and other sites. Clin Cancer Res. 2011;17(12):3933–42.

    Article  CAS  PubMed  Google Scholar 

  63. Schoenewolf NL, Bull C, Belloni B, Holzmann D, Tonolla S, Lang R, Mihic-Probst D, Andres C, Dummer R. Sinonasal, genital and acrolentiginous melanomas show distinct characteristics of KIT expression and mutations. Eur J Cancer. 2012;48(12):1842–52.

    Article  CAS  PubMed  Google Scholar 

  64. Curtin JA, Busam K, Pinkel D, Bastian BC. Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol. 2006;24(26):4340–46.

    Article  CAS  PubMed  Google Scholar 

  65. Kudchadkar RR, Smalley KS, Glass LF, Trimble JS, Sondak VK. Targeted therapy in melanoma. Clin Dermatol. 2013;31(2):200–8.

    Article  PubMed  Google Scholar 

  66. Ahn A, Eccles MR. Targeted therapy; from advanced melanoma to the adjuvant setting. Front Oncol. 2013;3:205.

    Article  PubMed Central  PubMed  Google Scholar 

  67. Busca R, Bertolotto C, Ortonne JP, Ballotti R. Inhibition of the phosphatidylinositol 3-kinase/p70(S6)-kinase pathway induces B16 melanoma cell differentiation. J Biol Chem. 1996;271(50):31824–30.

    Article  CAS  PubMed  Google Scholar 

  68. Dronca RS, Allred JB, Perez DG, Nevala WK, Lieser EA, Thompson M, Maples WJ, Creagan ET, Pockaj BA, Kaur JS, et al. Phase II study of temozolomide (TMZ) and everolimus (RAD001) therapy for metastatic melanoma: a North Central Cancer Treatment Group Study, N0675. Am J Clin Oncol. 2013;37(4):369–76.

    Article  CAS  Google Scholar 

  69. Margolin K, Longmate J, Baratta T, Synold T, Christensen S, Weber J, Gajewski T, Quirt I, Doroshow JH. CCI-779 in metastatic melanoma: a phase II trial of the California Cancer Consortium. Cancer. 2005;104(5):1045–8.

    Article  CAS  PubMed  Google Scholar 

  70. Grignol VP, Olencki T, Relekar K, Taylor C, Kibler A, Kefauver C, Wei L, Walker MJ, Chen HX, Kendra K, et al. A phase 2 trial of bevacizumab and high-dose interferon alpha 2B in metastatic melanoma. J Immunother. 2011;34(6):509–15.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  71. von Moos R, Seifert B, Simcock M, Goldinger SM, , Gillessen S, Ochsenbein A, Michielin O, Cathomas R, Schlappi M, Moch H, et al. First-line temozolomide combined with bevacizumab in metastatic melanoma: a multicentre phase II trial (SAKK 50/07). Ann Oncol. 2012;23(2):531–6.

    Article  Google Scholar 

  72. Perez DG, Suman VJ, Fitch TR, Amatruda T III, Morton RF, Jilani SZ, Constantinou CL, Egner JR, Kottschade LA, Markovic SN. Phase 2 trial of carboplatin, weekly paclitaxel, and biweekly bevacizumab in patients with unresectable stage IV melanoma: a North Central Cancer Treatment Group study, N047A. Cancer. 2009;115(1):119–27.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  73. Kim KB, Sosman JA, Fruehauf JP, Linette GP, Markovic SN, McDermott DF, Weber JS, Nguyen H, Cheverton P, Chen D, et al. 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(1):34–41.

    Article  CAS  PubMed  Google Scholar 

  74. Kottschade LA, Suman VJ, Perez DG, McWilliams RR, Kaur JS, Amatruda TT III, Geoffroy FJ, Gross HM, Cohen PA, Jaslowski AJ, et al. A randomized phase 2 study of temozolomide and bevacizumab or nab-paclitaxel, carboplatin, and bevacizumab in patients with unresectable stage IV melanoma: a North Central Cancer Treatment Group study, N0775. Cancer. 2013;119(3):586–92.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  75. El-Nassan HB. Recent progress in the identification of BRAF inhibitors as anti-cancer agents. Eur J Med Chem. 2014;72:170–205.

    Article  CAS  PubMed  Google Scholar 

  76. Flaherty KT, Lathia C, Frye RF, Schuchter L, Redlinger M, Rosen M, O’Dwyer PJ. Interaction of sorafenib and cytochrome P450 isoenzymes in patients with advanced melanoma: a phase I/II pharmacokinetic interaction study. Cancer Chemother Pharmacol. 2011;68(5):1111–8.

    Article  CAS  PubMed  Google Scholar 

  77. Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, Chen C, Zhang X, Vincent P, McHugh M, et al. 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(19):7099–109.

    Article  CAS  PubMed  Google Scholar 

  78. Wilhelm S, Carter C, Lynch M, Lowinger T, Dumas J, Smith RA, Schwartz B, Simantov R, Kelley S. Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov. 2006;5(10):835–44.

    Article  CAS  PubMed  Google Scholar 

  79. Bollag G, Hirth P, Tsai J, Zhang J, Ibrahim PN, Cho H, Spevak W, Zhang C, Zhang Y, Habets G, et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature. 2010;467(7315):596–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  80. Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, O'Dwyer PJ, Lee RJ, Grippo JF, Nolop K, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363(9):809–19.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  81. Dummer R, Goldinger SM, Turtschi CP, Eggmann NB, Michielin O, Mitchell L, Veronese L, Hilfiker PR, Felderer L, Rinderknecht JD. Vemurafenib in patients with BRAF(V600) mutation-positive melanoma with symptomatic brain metastases: final results of an open-label pilot study. Eur J Cancer. 2014;50(3):611–21.

    Article  CAS  PubMed  Google Scholar 

  82. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26):2507–16.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  83. Yang H, Higgins B, Kolinsky K, Packman K, Go Z, Iyer R, Kolis S, Zhao S, Lee R, Grippo JF, et al. RG7204 (PLX4032), a selective BRAFV600E inhibitor, displays potent antitumor activity in preclinical melanoma models. Cancer Res. 2010;70(13):5518–27.

    Article  CAS  PubMed  Google Scholar 

  84. Sosman JA, Kim KB, Schuchter L, Gonzalez R, Pavlick AC, Weber JS, McArthur GA, Hutson TE, Moschos SJ, Flaherty KT, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012;366(8):707–14.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  85. Young K, Minchom A, Larkin J. BRIM-1, -2 and -3 trials: improved survival with vemurafenib in metastatic melanoma patients with a BRAF(V600E) mutation. Future Oncol. 2012;8(5):499–507

    Article  CAS  PubMed  Google Scholar 

  86. Boyd KP, Vincent B, Andea A, Conry RM, Hughey LC. Nonmalignant cutaneous findings associated with vemurafenib use in patients with metastatic melanoma. J Am Acad Dermatol. 2012;67(6):1375–9.

    Article  CAS  PubMed  Google Scholar 

  87. Anforth R, Fernandez-Penas P, Long GV. Cutaneous toxicities of RAF inhibitors. Lancet Oncol. 2013;14(1):e11–8.

    Article  CAS  PubMed  Google Scholar 

  88. Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H, Chen Z, Lee MK, Attar N, Sazegar H, et al. 2010 Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature. 468(7326):973–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  89. Poulikakos PI, Persaud Y, Janakiraman M, Kong X, Ng C, Moriceau G, Shi H, Atefi M, Titz B, Gabay MT, et al. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature. 2011;480(7377):387–90.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  90. Paraiso KH, Xiang Y, Rebecca VW, Abel EV, Chen YA, Munko AC, Wood E, Fedorenko IV, Sondak VK, Anderson AR, et al. PTEN loss confers BRAF inhibitor resistance to melanoma cells through the suppression of BIM expression. Cancer Res. 2011;71(7):2750–60.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  91. Fedorenko IV, Paraiso KH, Smalley KS. Acquired and intrinsic BRAF inhibitor resistance in BRAF V600E mutant melanoma. Biochem Pharmacol. 2011;82(3):201–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  92. Sullivan RJ, Flaherty KT. Resistance to BRAF-targeted therapy in melanoma. Eur J Cancer. 2013;49(6):1297–304.

    Article  CAS  PubMed  Google Scholar 

  93. Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, Rutkowski P, Blank CU, Miller WH Jr, Kaempgen E, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380(9839):358–65.

    Article  CAS  PubMed  Google Scholar 

  94. Villanueva J, Vultur A, Lee JT, Somasundaram R, Fukunaga-Kalabis M, Cipolla AK, Wubbenhorst B, Xu X, Gimotty PA, Kee D, 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(6):683–95.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  95. Long GV, Trefzer U, Davies MA, Kefford RF, Ascierto PA, Chapman PB, Puzanov I, Hauschild A, Robert C, Algazi A, et al. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13(11):1087–95.

    Article  CAS  PubMed  Google Scholar 

  96. Falchook GS, Long GV, Kurzrock R, Kim KB, Arkenau TH, Brown MP, Hamid O, Infante JR, Millward M, Pavlick AC, et al. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet. 2012;379(9829):1893–901.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  97. Kainthla R, Kim KB, Falchook GS. Dabrafenib for treatment of BRAF-mutant melanoma. Pharmgenomics Pers Med. 2014;7:21–9.

    PubMed Central  PubMed  Google Scholar 

  98. Russo AE, Torrisi E, Bevelacqua Y, Perrotta R, Libra M, McCubrey JA, Spandidos DA, Stivala F, Malaponte G. Melanoma: molecular pathogenesis and emerging target therapies (Review). Int J Oncol. 2009;34(6):1481–9.

    CAS  PubMed  Google Scholar 

  99. Pratilas CA, Taylor BS, Ye Q, Viale A, Sander C, Solit DB, Rosen N. (V600E)BRAF is associated with disabled feedback inhibition of RAF-MEK signaling and elevated transcriptional output of the pathway. Proc Natl Acad Sci U S A. 2009;106(11):4519–24.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  100. Flaherty KT, Hodi FS, Bastian BC. Mutation-driven drug development in melanoma. Curr Opin Oncol. 2010;22(3):178–83.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  101. Solit DB, Garraway LA, Pratilas CA, Sawai A, Getz G, Basso A, Ye Q, Lobo JM, She Y, Osman I, et al. BRAF mutation predicts sensitivity to MEK inhibition. Nature. 2006;439(7074):358–62.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  102. Lorusso PM, Adjei AA, Varterasian M, Gadgeel S, Reid J, Mitchell DY, Hanson L, DeLuca P, Bruzek L, Piens J, et al. Phase I and pharmacodynamic study of the oral MEK inhibitor CI-1040 in patients with advanced malignancies. J Clin Oncol. 2005;23(23):5281–93.

    Article  CAS  PubMed  Google Scholar 

  103. Kirkwood JM, Bastholt L, Robert C, Sosman J, Larkin J, Hersey P, Middleton M, Cantarini M, Zazulina V, Kemsley K, 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. 2012;18(2):555–67.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  104. Ascierto PA, Schadendorf D, Berking C, Agarwala SS, van Herpen CM, Queirolo P, Blank CU, Hauschild A, Beck JT, St-Pierre 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. 2013;14(3):249–56.

    Article  CAS  PubMed  Google Scholar 

  105. Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, Demidov LV, Hassel JC, Rutkowski P, Mohr P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367:107–14.

    Article  CAS  PubMed  Google Scholar 

  106. Grimaldi AM, Simeone E, Ascierto PA. The role of MEK inhibitors in the treatment of metastatic melanoma. Curr Opin Oncol. 2014;26(2):196–203.

    Article  CAS  PubMed  Google Scholar 

  107. Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, Hamid O, Schuchter L, Cebon J, Ibrahim N, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367(18):1694–703.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  108. Menzies AM, Long GV. Dabrafenib and trametinib, alone and in combination for BRAF-mutant metastatic melanoma. Clin Cancer Res. 2014;20:2035–43.

    Article  CAS  PubMed  Google Scholar 

  109. Carvajal RD, Antonescu CR, Wolchok JD, Chapman PB, Roman RA, Teitcher J, Panageas KS, Busam KJ, Chmielowski B, Lutzky J, et al. KIT as a therapeutic target in metastatic melanoma. JAMA. 2011;305(22):2327–34.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  110. Guo J, Si L, Kong Y, Flaherty KT, Xu X, Zhu Y, Corless CL, Li L, Li H, Sheng X, 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(21):2904–9.

    Article  CAS  PubMed  Google Scholar 

  111. Wyman K, Atkins MB, Prieto V, Eton O, McDermott DF, Hubbard F, Byrnes C, Sanders K, Sosman JA. Multicenter Phase II trial of high-dose imatinib mesylate in metastatic melanoma: significant toxicity with no clinical efficacy. Cancer. 2006;106(9):2005–11.

    Article  CAS  PubMed  Google Scholar 

  112. Ugurel S, Hildenbrand R, Zimpfer A, La Rosee P, Paschka P, Sucker A, Keikavoussi P, Becker JC, Rittgen W, Hochhaus A, et al. Lack of clinical efficacy of imatinib in metastatic melanoma. Br J Cancer. 2005;92(8):1398–405.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  113. Hodi FS, Friedlander P, Corless CL, Heinrich MC, Mac Rae S, Kruse A, Jagannathan J, Van den Abbeele AD, Velazquez EF, Demetri GD, et al. Major response to imatinib mesylate in KIT-mutated melanoma. J Clin Oncol. 2008;26(12):2046–51.

    Article  CAS  PubMed  Google Scholar 

  114. Hodi FS, Corless CL, Giobbie-Hurder A, Fletcher JA, Zhu M, Marino-Enriquez A, Friedlander P, Gonzalez R, Weber JS, Gajewski TF, et al. Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun-damaged skin. J Clin Oncol. 2013;31(26):3182–90.

    Article  CAS  PubMed  Google Scholar 

  115. Alexandrescu DT, Ichim TE, Riordan NH, Marincola FM, Di Nardo A, Kabigting FD, Dasanu CA. Immunotherapy for melanoma: current status and perspectives. J Immunother. 2010;33(6):570–90.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  116. Rosenberg SA, Mule JJ, Spiess PJ, Reichert CM, Schwarz SL. Regression of established pulmonary metastases and subcutaneous tumor mediated by the systemic administration of high-dose recombinant interleukin 2. J Exp Med. 1985;161(5):1169–88.

    Article  CAS  PubMed  Google Scholar 

  117. Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, Abrams J, Sznol M, Parkinson D, Hawkins M, et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999;17(7):2105–16.

    CAS  PubMed  Google Scholar 

  118. Hauschild A. Adjuvant interferon alfa for melanoma: new evidence-based treatment recommendations? Curr Oncol. 2009;16(3):3–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  119. Iida T, Ohno H, Nakaseko C, Sakuma M, Takeda-Ezaki M, Arase H, Kominami E, Fujisawa T, Saito T. Regulation of cell surface expression of CTLA-4 by secretion of CTLA-4-containing lysosomes upon activation of CD4 + T cells. J Immunol. 2000;165(9):5062–8.

    Article  CAS  PubMed  Google Scholar 

  120. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–23.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  121. Della Vittoria Scarpati G, Fusciello C, Perri F, Sabbatino F, Ferrone S, Carlomagno C, Pepe S. Ipilimumab in the treatment of metastatic melanoma: management of adverse events. Oncol Targets Ther. 2014;7:203–9.

    Article  CAS  Google Scholar 

  122. Margolin K, Ernstoff MS, Hamid O, Lawrence D, McDermott D, Puzanov I, Wolchok JD, Clark JI, Sznol M, Logan TF, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 2012;13(5):459–65.

    Article  CAS  PubMed  Google Scholar 

  123. Ascierto PA. Ipilimumab in the treatment of metastatic melanoma: a summary of recent studies. Tumori. 2013;99(6):302e–5

    Google Scholar 

  124. Ascierto PA, Marincola FM, Ribas A. Anti-CTLA4 monoclonal antibodies: the past and the future in clinical application. J Transl Med. 2011;9:196.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  125. Riley JL. PD-1 signaling in primary T cells. Immunol Rev. 2009;229(1):114–25.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  126. Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 1992;11(11):3887–95.

    PubMed Central  CAS  PubMed  Google Scholar 

  127. Nishimura H, Honjo TÂ. PD-1: an inhibitory immunoreceptor involved in peripheral tolerance. Trends Immunol. 2001;22(5):265–8.

    Article  CAS  PubMed  Google Scholar 

  128. Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, Linsley PS, Thompson CB, Riley JL. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol. 2005;25(21):9543–53.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  129. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–54.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  130. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455–65.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  131. Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, Wolchok JD, Hersey P, Joseph RW, Weber JS, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013;369(2):134–44.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Via Del Vespro 127, 90127, Palermo, Italy

    Daniele Fanale, Giuseppe Bronte MD, Phd & Antonio Russo

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  1. Daniele Fanale
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  2. Giuseppe Bronte MD, Phd
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  3. Antonio Russo
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Correspondence to Giuseppe Bronte MD, Phd .

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Editors and Affiliations

  1. Department of Surgical, Oncological and Oral Sciences, University of Palermo, Palermo, Italy

    Antonio Russo

  2. Catalan Institute of Oncology, University Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain

    Rafael Rosell

  3. Oncology Department, Antwerp University Hospital, Edegem, Antwerpen, Belgium

    Christian Rolfo

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Fanale, D., Bronte, G., Russo, A. (2015). Targeted Therapies in Melanoma. In: Russo, A., Rosell, R., Rolfo, C. (eds) Targeted Therapies for Solid Tumors. Current Clinical Pathology. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-2047-1_16

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