Current status of biological therapies for the treatment of metastatic melanoma

Anticancer Research

Volumn 36, Issue 7, 2016, Pages 3229-3241

  Tang, Tianyi ^a   Eldabaje, Robert ^a   Yang, Lixi ^b  

^a ST MARY S MEDICAL CENTER   (United States)

^b CALIFORNIA PACIFIC MEDICAL CENTER   (United States)

Author keywords

DNA methylation; Histone modification; Immunotherapy; Metastatic melanoma; MicroRNA; Review; Targeted therapy

Indexed keywords

ALDESLEUKIN; B RAF KINASE INHIBITOR; COBIMETINIB; CYCLIN DEPENDENT KINASE 4; CYCLIN DEPENDENT KINASE 6; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; DABRAFENIB; DACARBAZINE; GLYCOPROTEIN GP 100 VACCINE; GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR; GUANINE NUCLEOTIDE BINDING PROTEIN ALPHA SUBUNIT; IMATINIB; IMIQUIMOD; INTERLEUKIN 2; IPILIMUMAB; MITOGEN ACTIVATED PROTEIN KINASE KINASE INHIBITOR; NILOTINIB; NIVOLUMAB; ONCOLYTIC VIRUS; PEMBROLIZUMAB; PEPTIDE VACCINE; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PROGRAMMED DEATH 1 LIGAND 1; PROTEIN TYROSINE KINASE INHIBITOR; RETINOID; TALIMOGENE LAHERPAREPVEC; TOLL LIKE RECEPTOR; TRAMETINIB; UNCLASSIFIED DRUG; UNINDEXED DRUG; VEMURAFENIB;

ADOPTIVE IMMUNOTHERAPY; ANTINEOPLASTIC ACTIVITY; BIOLOGICAL THERAPY; CANCER IMMUNOTHERAPY; CANCER SURVIVAL; DNA METHYLATION; DRUG EFFICACY; DRUG MECHANISM; DRUG TARGETING; GENE CONTROL; GENE MUTATION; HISTONE MODIFICATION; HUMAN; METASTATIC MELANOMA; MOLECULARLY TARGETED THERAPY; NONHUMAN; ONCOLYTIC VIROTHERAPY; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; T LYMPHOCYTE; TREATMENT OUTCOME; ANIMAL; IMMUNOLOGY; MELANOMA; PROCEDURES; VIROLOGY;

ANIMALS; BIOLOGICAL THERAPY; HUMANS; IMMUNOTHERAPY, ADOPTIVE; MELANOMA; ONCOLYTIC VIROTHERAPY;

EID: 84992108908     PISSN: 02507005     EISSN: 17917530     Source Type: Journal    
DOI: None     Document Type: Review

References (105)

1. Hollenbeak CS, Todd MM, Billingsley EM, Harper G, Dyer AM and Lengerich EJ: Increased incidence of melanoma in renal transplantation recipients. Cancer 104(9): 1962-1967, 2005.
2. Oble DA, Loewe R, Yu P and Mihm MC Jr.: Focus on TILs: Prognostic significance of tumor infiltrating lymphocytes in human melanoma. Cancer Immun 9(3): 1-20, 2009.
3. Rodeck U and Herlyn M: Growth factor in melanoma. Cancer Metastasis Rev 10(2): 89-101, 1991.
4. Elias EG, Hasskamp JH and Sharma BK: Cytokines and growth factors expressed by human cutaneous melanoma. Cancers (Basel) 2(2): 794-808, 2010.
5. Bracher A, Cardona AS, Tauber S, Fink AM, Steiner A, Pehamberger H, Niederleithner H, Petzelbauer P, Gröger M and Loewe R: Epidermal growth factor facilitates melanoma lymph node metastasis by influencing tumor lymphangiogenesis. J Invest Dermatol 133(1): 230-238, 2013.
6. Polsky D and Cordon-Cardo C: Oncogenes in melanoma. Oncogene 22(20): 3087-3091, 2003.
7. Snyder A, Makarov V, Mergoub T, Yuan J, Zaretsky JM, Desrichard A, Walsh LA, Postow MA, Wong P, Ho TS, Hollmann TJ, Bruggeman C, Kannan K, Li Y, Elipenahli C, Liu C, Harbison CT, Wang L, Ribas A, Wolchok JD and Chan TA: Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 371(23): 2189-2199, 2014.
8. Dunn GP, Old LJ and Schreiber RD: The three Es of cancer immunoediting. Annu Rev Immunol 22: 329-360, 2004.
9. Igney FH and Krammer PH: Immune escape of tumors: Apoptosis resistance and tumor counterattack. J Leukoc Biol 71(6): 907-920, 2002.
10. Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, Abrams J, Sznol M, Parkinson D, Hawkins M, Paradise C, Kunkel L and Rosenberg SA: High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: Analysis of 270 patients treated between 1985-1993. J Clin Oncol 17(7): 2105-2116, 1999.
11. Radny P, Caroli UM, Bauer J, Paul T, Schlegel C, Eigentler TK, Weide B, Schwarz M and Garbe C: Phase II trial of intralesional therapy with interleukin-2 in soft-tissue melanoma metastases. Br J Cancer 89(9): 1620-1626, 2003.
12. Weide B, Eigentler TK, Pflugfelder A, Leiter U, Meier F, Bauer J, Schmidt D, Radny P, Pföhler C and Garbe C: Survival after intratumoral interleukin-2 treatment of 72 melanoma patients and response upon the first chemotherapy during follow-up. Cancer Immunol Immunother 60(4): 487-493, 2011.
13. Sim GC, Martin-Orozco N, Jin L, Yang Y, Wu S, Washington E, Sanders D, Lacey C, Wang Y, Vence L, Hwu P and Radvanyi L: IL-2 therapy promotes suppressive ICOS+ Treg expansion in melanoma patients. J Clin Invest 124(1): 99-110, 2014.
14. Schwartzentruber DJ, Lawson DH, Richards JM, Conry RM, Miller DM, Treisman J, Gailani F, Riley L, Conlon K, Pockaj B, Kendra KL, White RL, Gonzalez R, Kuzel TM, Curti B, Leming PD, Whitman ED, Balkissoon J, Reintgen DS, Kaufman H, Marincola FM, Merino MJ, Rosenberg SA, Choyke P, Vena D and Hwu P: Gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma. N Engl J Med 364(22): 2119-2127, 2011.
15. Butte MJ, Peña-Cruz V, Kim MJ, Freeman GJ and Sharpe AH: Interaction of human PD-L1 and B7-1. Mol Immunol 45(13): 3567-3572, 2008.
16. Chapon M, Randriamampita C, Maubec E, Badoual C, Fouquet S, Wang SF, Marinho E, Farhi D, Garcette M, Jacobelli S, Rouquette A, Carlotti A, Girod A, Prévost-Blondel A, Trautmann A, Avril MF and Bercovici N: Progressive upregulation of PD-1 in primary and metastatic melanomas associated with blunted TCR signaling in infiltrating T lymphocytes. J Invest Dermatol 131(6): 1300-1307, 2011.
17. 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, Lebbé C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A and Urba WJ: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363(8): 711-723, 2010.
18. Weber J: Ipilimumab: Controversies in its development, utility and autoimmune adverse events. Cancer Immunol Immunother 58(5): 823-830, 2009.
19. O'Day SJ, Maio M, Chiarion-Sileni V, Gajewski TF, Pehamberger H, Bondarenko IN, Queirolo P, Lundgren L, Mikhailov S, Roman L, Verschraegen C, Humphrey R, Ibrahim R, De Pril V, Hoos A and Wolchok JD: Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: A multicenter single-arm phase II study. Ann Oncol 21(8): 1712-1717, 2010.
20. Robert C, Thomas L, Bondarenko I, O'Day S, Weber J, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller WH Jr., Gascon P, Loterm M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A and Wolchok JD: Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364(26): 2517-2526, 2011.
21. Prieto PA, Yang JC, Sherry RM, Hughes MS, Kammula US, White DE, Levy CL, Rosenberg SA and Phan GQ: CTLA-4 blockade with ipilimumab: Long-term follow-up of 177 patients with metastatic melanoma. Clin Cancer Res 18(7): 2039-2047, 2012.
22. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel Dr, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM and Sznol M: Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366(26): 2443-2454, 2012.
23. Topalian SL, Sznol M, McDermott DF, Kluger HM, Carvajal RD, Sharfman WH, Brahmer JR, Lawrence DP, Atkins MB, Powderly JD, Leming PD, Lipson EJ, Puzanov I, Smith DC, Taube JM, Wigginton JM, Kollia GD, Gupta A, Pardoll DM, Sosman JA and Hodi FS: Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol 32(10): 1020-1030, 2014.
24. Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbé C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Arance A, Schmidt H, Schadendorf D, Gogas H, Lundgren-Eriksson L, Horak C, Sharkey B, Waxman IM, Atkinson V and Ascierto PA: Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 372(4): 320-330, 2015.
25. Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, Hoeller C, Khushalani NI, Miller WH Jr, Lao CD, Linette GP, Thomas L, Lorigan P, Grossman KF, Hassel JC, Maio M, Sznol M, Ascierto PA, Mohr P, Chmielowski B, Bryce A, Svane IM, Grob JJ, Krackhardt AM, Horak C, Lambert A, Yang AS and Larkin J: Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): A randomised, controlled, openlabel, phase 3 trial. Lancet Oncol 16(4): 375-384, 2015.
26. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS and Wolchok JD: Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 373(1): 23-34, 2015.
27. Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S and Ribas A: Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 372(26): 2521-2532, 2015.
28. Hemmi H, Kaisho T, Takeuchi O, Sato S, Sanjo H, Hoshino K, Horiuchi T, Tomizawa H, Takeda K and Akira S: Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol 3(2): 196-200, 2002.
29. Bilu D and Sauder DN: Imiquimod: Modes of action. Br J Dermatol 149(Suppl 66): 5-8, 2003.
30. Narayan R, Nguyen H, Bentow JJ, Moy L, Lee DK, Greger S, Haskell J, Vanchinathan V, Chang PL, Tsui S, Konishi T, Comin-Anduix B, Dauphine C, Vargas HI, Economou JS, Ribas A, Bruhn KW and Craft N: Immunomodulation by imiquimod in patients with high-risk primary melanoma. J Invest Dermatol 132(1): 163-169, 2012.
31. Wolf IH, Smolle J, Binder B, Cerroni L, Richtig E and Kerl H: Topical imiquimod in the treatment of metastatic melanoma to skin. Arch Dermatol 139(3): 273-276, 2003.
32. Ellis LZ, Cohen JL, High W and Stewart L: Melanoma in situ treated successfully using imiquimod after nonclearance with surgery: Review of the literature. Dermatol Surg 38(6): 937-946, 2012.
33. Turza K, Dengel LT, Harris RC, Patterson JW, White K, Grosh WW and Slingluff CL Jr: Effectiveness of imiquimod limited to dermal melanoma metastases with simultaneous resistance of subcutaneous metastasis. J Cutan Pathol 37(1): 94-98, 2010.
34. Shi VY, Tran K, Patel F, Leventhal J, Konia T, Fung MA, Wilken R, Garcia MS, Fitzmaurice SD, Joo J, Monjazeb AM, Burrall BA, King B, Martinez S, Christensen SD and Maverakis E: 100% Complete response rate in patients with cutaneous metastatic melanoma treated with intralesional interleukin (IL)-2, imiquimod, and topical retinoid combination therapy: Results of a case series. J Am Acad Dermatol 73(4): 645-654, 2015.
35. Wu R, Forget MA, Chacon J, Bernatchez C, Haymaker C, Chen JQ Hwu P and Radvanyi LG: Adoptive T-cell therapy using autologous tumor-infiltrating lymphocytes for metastatic melanoma: Current status and future outlook. Cancer J 18(2): 160-175, 2012.
36. Rosenberg SA: Cell transfer immunotherapy for metastatic solid cancer-what clinicians need to know. Nat Rev Clin Oncol 8(10): 577-585, 2011.
37. Rosenberg SA, Yang JC, Sherry RM, Kammula US, Hughes MS, Phan GC, Citrin DE, Restifo NP, Robbins PF, Wunderlich JR, Morton KE, Laurencot CM, Steinberg SM, White DE and Dudley ME: Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res 17(13): 4550-4557, 2011.
38. Joseph RW, Peddareddigari VR, Liu P, Miler PW, Overwijk WW, Bekele NB, Ross MI, Lee JE, Gershenwald JE, Lucci A, Prieto VG, McMannis JD, Papadopoulos N, Kim K, Homsi J, Bedikian A, Hwu WJ, Hwu P and Radvanyi LG: Impact of clinical and pathologic features on tumor-infiltrating lymphocyte expansion from surgically excised melanoma metastases for adoptive T-cell therapy. Clin Cancer Res 17(14): 4882-4891, 2011.
39. Bartkowiak T and Curran MA: 4-1BB Agonists: Multi-potent potentiators of tumor immunity. Front Oncol 5: 117, 2015.
40. Ellebaek E, Iversen TZ, Junker N, Donia M, Engell-Noerregaard L, Met Ö, Hölmich LR, Andersen RS, Hadrup SR, Andersen MH, thor Straten P and Svane IM: Adoptive cell therapy with autologous tumor infiltrating lymphocytes and low-dose interleukin-2 in metastatic melanoma patients. J Transl Med 10: 169, 2012.
41. Hu-Lieskovan S, Robert L, Homet Moreno B and Ribas A: Combining targeted therapy with immunotherapy in BRAFmutant melanoma: Promise and challenges. J Clin Oncol 32(21): 2248-2254, 2014.
42. Koya RC, Mok S, Otte Blacketor KJ, Comin-Anduix B, Tumeh PC, Minasyan A, Graham NA, Graeber TG, Chodon T and Ribas A: BRAF inhibitor vemurafenib improves the antitumor activity of adoptive cell immunotherapy. Cancer Res 72(16): 3928-3927, 2012.
43. Chiocca EA and Rabkin SD: Oncolytic viruses and their application to cancer immunotherapy. Cancer Immunol Res 2(4): 295-300, 2014.
44. Frentzen A, Yu YA, Chen N, Zhang Q, Weibel S, Raab V and Szalay AA: Anti-VEGF single-chain antibody GLAF-1 encoded by oncolytic vaccinia virus significantly enhances antitumor therapy. Proc Natl Acad Sci USA 106(31): 12915-12920, 2009.
45. Conner J and Braidwood L: Expression of inhibitor of growth 4 by HSV1716 improves oncolytic potency and enhances efficacy. Cancer Gene Ther 19(7): 499-507, 2012.
46. Bartlett DL, Liu Z, Sathaiah M, Ravindranathan R, Guo Z, He Y and Guo ZS: Oncolytic viruses as therapeutic cancer vaccines. Mol Cancer 12(1): 103, 2013.
47. Kaufman HL, Kim DW, DeRaffele G, Mitcham J, Coffin RS and Kim-Schulze S: Local and distant immunity induced by intralesional vaccination with an oncolytic herpes virus encoding GM-CSF in patients with stage IIIc and IV melanoma. Ann Surg Oncol 17(3): 718-730, 2010.
48. Andtbacka RH, Kaufman HL, Collichio F, Amatruda T, Senzer N, Chesney J, Delman KA, Spitler, LE, Puzanov I, Agarwala SS, Milhem M, Cranmer L, Curti B, Lewis K, Ross M, Guthrie T, Linette GP, Daniels GA, Harrington K, Middleton MR, Miller WH Jr, Zager JS, Ye Y, Yao B, Li A, Doleman S, VanderWalde A, Gansert J and Coffin RS: Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol 33(25): 2780-2788, 2015.
49. 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, How JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR and Futreal PA: Mutations of the BRAF gene in human cancer. Nature 417(6892): 949-954, 2002.
50. Cantwell-Dorris ER, O'Leary JJ and Sheils OM: BRAFV600E: Implications for carcinogenesis and molecular therapy. Mol Cancer Ther 10(3): 385-394, 2011.
51. 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 and Bollag G: Discovery of a selective inhibitor of oncogenic BRaf kinase with potent antimelanoma activity. Proc Natl Acad Sci USA 105(8): 3041-3046, 2008.
52. 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 and Malek S: RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 464(28): 431-435, 2010.
53. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, Hogg D, Lorigan P, Lebbe C, Jouary T, Schadendorf D, RIbas A, O'Day SJ, Sosman JA, Kirkwood JM, Eggermont AM, Dreno B, Nolop K, Li J, Nelson B, Hou J, Lee RJ, Flaherty KT and McArthur GA: Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364(26): 2507-2516, 2011.
54. Montagut C, Sharma SV, Shioda T, McDermott U, Ulman M, Ulkus LE, Dias-Santagata D, Stubbs H, Lee DY, Singh A, Drew L, Habet DA and Settleman J: Elevated CRAF as a potential mechanism of acquired resistance to BRAF inhibition in melanoma. Cancer Res 68(12): 4853-4861, 2008.
55. 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 and Garraway LA: COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 468(7326): 968-972, 2010.
56. Larkin J, Ascierto PA, Dréno B, Atkinson V, Liszkay G, Maio M, Mandalà M, Demidov L, Stroyakovskiy D, Thomas L, de la Cruz-Merino L, Dutriaux C, Garbe C, Sovak MA, Chang I Choong N, Hack SP, McArthur GA and Ribas A: Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med 371(20): 1867-1876, 2014.
57. Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, Rutkowski P, Blank CU, Miller WH Jr, Kaempgen E, Martín-Algarra S, Karaszewska B, Mauch C, Chiarion-Sileni V, Martin AM, Swann S, Haney P, Mirakhur B, Guckert ME, Goodman V and Chapman PB: Dabrafenib in BRAF-mutated metastatic melanoma: A multicenter, open-label, phase 3 randomised controlled trial. Lancet 380(9839): 358-365, 2012.
58. Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, Garbe C, Jouary T, Hasuchild A, Grob JJ, Chiarion-Sileni V, Lebbe C, Mandalà M, Millward M, Arance A, Bondarenko I, Haanen JB, Hansson J, Utikal J, Ferraresi V, Kovalenko N, Mohr P, Probachai V, Schadendorf D, Nathan P, Robert C, Ribas A, DeMarini DJ, Irani JG, Swann S, Legos JJ, Jin F, Mookerjee B and Flaherty K: Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: A multicenter, double-blind, phase 3 randomised controlled trial. Lancet 386(9992): 444-451, 2015.
59. Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, Lichinitser M, Dummer R, Grange F, Mortier L, Chiarion-Sileni V, Drucis K, Krajsova I, Hauschild A, Lorigan P, Wolter P, Long GV, Flaherty K, Nathan P, Ribas A, Martin AM, Sun P, Crist W, Legos J, Rubin SD, Little SM and Schadendorf D: Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med 372(1): 30-39, 2015.
60. Wagle N, Emery C, Berger MF, Davis MJ, Sawyer A, Pochanard P, Kehoe SM, Johannessen CM, Macconaill LE, Hahn WC, Meyerson M and Garraway LA: Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling. J Clin Oncol 29(22): 3085-3096, 2011.
61. Wagle N, Van Allen EM, Treacy DJ, Frederick DT, Cooper ZA, Taylor-Weiner A, Rosenberg M, Goetz EM, Sullivan RJ, Farlow DN, Friedrich DC, Anderka K, Perrin D, Johannessen CM, McKenna A, Cibulskis K, Kryukov G, Hodis E, Lawrence DP, Fisher S, Getz G, Gabriel SB, Carter SL, Flaherty KT, Wargo JA and Garraway LA: MAP kinase pathway alterations in BRAFmutant melanoma patients with acquired resistance to combined RAF/MEK inhibition. Cancer Discov 4(1): 61-68, 2014.
62. Villanueva J, Vultur A, Lee JT, Somasundaram R, Fukunaga-Kalabis M, Cipolla AK, Wubbenhorst B, Xu X, Gimotty PA, Kee D, Santiago-Walker AE, Letrero R, D'Andrea K, Pushparajan A, Hayden JE, Brown KD, Laquerre S, McArthur GA, Sosman JA, Nathanson KL and Herlyn M: 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 18(6): 683-695, 2010.
63. Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H, Chen Z, Lee MK, Attar N, Sazegar H, Chodon T, Nelson SF, McArthur G, Sosman JA, Ribas A and Lo RS: Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 468(7326): 973-977, 2010.
64. Curtin JA, Busam K, Pinkel D and Bastian BC: Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol 24(26): 4340-4346, 2006.
65. Beadling C, Jacobson-Dunlop E, Hodi FS, Le C, Warrick A, Patterson J, Town A, Harlow A, Cruz F III, Azar S, Rubin BP, Muller S, West R, Heinrich MC and Corless CL: KIT gene mutations and copy number in melanoma subtypes. Clin Cancer Res 14(21): 6821-6828, 2008.
66. Carvajal RD, Antonescu CR, Wolchok JD, Chapman PB, Roman RA, Teitcher J, Panageas KS, Busam KJ, Chmielowski B, Lutzky J, Pavlick AC, Fusco A, Cane L, Takebe N, Vemula S, Bouvier N, Bastian BC and Schwartz GK: KIT as a therapeutic target in metastatic melanoma. JAMA 305(22): 2327-2334, 2011.
67. 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 and 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 29(21): 2904-2909, 2011.
68. Carvajal RD, Lawrence DP, Weber JS, Gajewski TF, Gonzalez R, Lutzky J, O'Day SJ, Hamid O, Wolchok JD, Chapman PB, Sullivan RJ, Teitcher JB, Ramaiya N, Giobbie-Hurder A, Antonescu CR, Heinrich MC, Bastian BC, Corless CL, Fletcher JA and Hodi FS: Phase II study of nilotinib in melanoma harboring KIT alterations following progression to prior KIT inhibition. Clin Cancer Res 21(10): 2289-2296, 2015.
69. de Wit PE, Moretti S, Koenders PG, Weterman MA, van Muijen GN, Gianotti B and Ruiter DJ: Increasing epidermal growth factor receptor expression in human melanocytic tumor progression. J Invest Dermatol 99(2): 168-173, 1992.
70. Girotti MR, Pedersen M, Sanchez-Laorden B, Viros A, Turajlic S, Niculescu-Duvaz D, Zambon A, Sinclair J, Hayes A, Gore M, Lorigan P, Springer C, Larkin J, Jorgensen C and Marais R: Inhibiting EGF receptor or SRC family kinase signaling overcomes BRAF inhibitor resistance in melanoma. Cancer Discov 3(2): 158-167, 2013.
71. Sun C, Wang L, Huang S, Heynen GJ, Prahallad A, Robert C, Haanen J, Blank C, Wesseling J, Willems SM, Zecchin D, Hobor S, Bajpe PK, Lieftink C, Mateus C, Vagner S, Grernrum W, Hofland I, Schlicker A, Wessels LF, Beijersbergen RL, Bardelli A, Di Nicolantonio F, Eggermont AM and Bernards R: Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma. Nature 508(7494): 118-122, 2014.
72. Fedorenko IV, Fang B, Munko AC, Gibney GT, Koomen JM and Smalley KS: Phosphoproteomic analysis of basal and therapyinduced adaptive signaling networks in BRAF and NRAS mutant melanoma. Proteomics 15(2-3): 327-339, 2015.
73. Ball NJ, Yohn JJ, Morelli JG, Norris DA, Golitz LE and Hoeffler JP: Ras mutations in human melanoma: A marker of malignant progression. J Invest Dermatol 102(3): 285-290, 1994.
74. Devitt B, Liu W, Salemi R, Wolfe R, Kelly J, Tzen CY, Dobrovic A and McArthur G: Clinical outcome and pathological features associated with NRAS mutation in cutaneous melanoma. Pigment Cell Melanoma Res 24(4): 666-672, 2011.
75. Jakob JA, Bassett RL Jr., Ng CS, Curry JL, Joseph RW, Alvarado GC, Rohlfs ML, Richard J, Gershenwald JE, Kim KB, Lazar AJ, Hwu P and Davies MA: NRAS mutation status is an independent prognostic factor in metastatic melanoma. Cancer 118(16): 4014-4023, 2012.
76. Ekedahl H, Cirenajwis H, Harbst K, Carneiro A, Nielsen K, Olsson H, Lundgren L, Ingvar C and Jönsson G: The clinical significance of BRAF and NRAS mutations in a clinic-based metastatic melanoma cohort. Br J Dermatol 169(5): 1049-1055, 2013.
77. Lidsky M, Antoun G, Speicher P, Adams B, Turley R, Augustine C, Tyler D and Ali-Osman F: Mitogen-activated protein kinase (MAPK) hyperactivation and enhanced NRAS expression drive acquired vemurafenib resistance in V600E BRAF melanoma cells. J Biol Chem 289(40): 27714-27726, 2014.
78. Walker GJ, Flores JF, Glendening JM, Lin AH, Markl ID and Fountain JW: Virtually 100% of melanoma cell lines harbor alterations at the DNA level within CDKN2A, CDKN2B, or one of their downstream targets. Genes Chromosomes Cancer 22(2): 157-163, 1998.
79. Curtin JA, Fridlyand J, Kageshita T, Patel HN, Busam KJ, Kutzner H, Cho KH, Aiba S, Bröcker EB, LeBoit PE, Pinkel D and Bastian BC: Distinct sets of genetic alterations in melanoma. N Engl J Med 353(20): 2135-2147, 2005.
80. Aguissa-Touré AH and Li G: Genetic alterations of PTEN in human melanoma. Cell Mol Life Sci 69(9): 1475-1491, 2012.
81. Tsao H, Chin L, Garraway LA and Fisher DE: Melanoma: From mutations to medicine. Genes Dev 26(11): 1131-1155, 2012.
82. Dankort D, Curley DP, Cartlidge RA, Nelson B, Karnezis AN, Damsky WE Jr, You MJ, DePinho RA, McMahon M and Bosenberg M: Braf(V600E) cooperates with Pten loss to induce metastatic melanoma. Nat Genet 41(5): 544-552, 2009.
83. Cohen Y, Goldenberg-Cohen N, Parrella P, Chowers I, Merbs SL, Pe'er J and Sidransky D: Lack of BRAF mutation in primary uveal melanoma. Invest Ophthalmol Vis Sci 44(7): 2876-2878, 2003.
84. Cruz F III, Rubin BP, Wilson D, Town A, Schroeder A, Haley A, Bainbridge T, Heinrich MC and Corless CL: Absence of BRAF and NRAS mutations in uveal melanoma. Cancer Res 63(18): 5761-5766, 2003.
85. Weber A, Hengge D, Urbanik D, Markwart A, Mirmohammadsaegh A, Reichel MB, Wittekind C, Wiedemann P and Tannapfel A: Absence of mutations of the BRAF gene and constitutive activation of extracellular-regulated kinase in malignant melanomas of the uvea. Lab Invest 83(12): 1771-1776, 2003.
86. Pópulo H, Vinagre J, Lopes JM and Soares P: Analysis of GNAQ mutations, proliferation and MAPK pathway activation in uveal melanomas. Br J Ophthalmol 95(5): 715-719, 2011.
87. Gessi M, Hammes J, Lauriola L, Dörner E, Kirfel J, Kristiansen G, zur Muehlen A, Denkhaus D, Waha A and Pietsch T: GNA11 and N-RAS mutations: Alternatives for MAPK pathway activating GNAQ mutations in primary melanocytic tumours of the central nervous system. Neuropathol Appl Neurobiol 39(4): 417-425, 2013.
88. Das PM and Singal R: DNA methylation and cancer. J Clin Oncol 22(22):4632-4642, 2004.
89. Straume O, Smeds J, Kumar R, Hemminki K and Akslen LA: Significant impact of promoter hypermethylation and the 540 C>T polymorphism of CDKN2A in cutaneous melnaoma of the vertical growth phase. Am J Pathol 161(1): 229-237, 2002.
90. Hoon DS, Spugnardi M, Kuo C, Huang SK, Morton DL and Taback B: Profiling epigenetic inactivation of tumor suppressor genes in tumors and plasma from cutaneous melanoma patients. Oncogene 23(22): 4014-4022, 2004.
91. Mirmohammadsadegh A, Marini A, Namiar S, Hassan M, Tannapfel A, Ruzicka T and Hengge UR: Epigenetic silencing of the PTEN gene in melanoma. Cancer Res 66(13): 6546-6552, 2006.
92. Tanemura A, Terando AM, Sim MS, van Hoesel AQ, de Maat MF, Morton DL and Hoon DS: CpG island methylator phenotype predicts progression of malignant melanoma. Clin Cancer Res 15(5): 1801-1807, 2009.
93. Rubinstein JC, Tran N, Ma S, Halaban R and Krauthammer M: Genome-wide methylation and expression profiling identifies promoter characteristics affecting demethylation-induced gene up-regulation in melanoma. BMC Med Genomics 3: 4, 2010.
94. Boyle GM, Martyn AC and Parsons PG: Histone deacetylase inihibitors and malignant melanoma. Pigment Cell Res 18(3): 160-166, 2005.
95. Nihal M, Roelke CT and Wood GS: Anti-melanoma effects of vorinostat in combination with polyphenolic antioxidant (-)-epigallocatechin-3-gallate (EGCG). Pharm Res 27(6): 1104-1114, 2010.
96. Yajima I, Kumasaka MY, Thang ND, Goto Y, Takeda K, Iida M, Ohgami N, Tamura H, Yamanoshita O, Kawamoto Y, Furukawa K and Kato M: Molecular network associated with MITF in skin melanoma development and progression. J Skin Cancer 2011: 730170, 2011.
97. Garraway LA, Widlund HR, Rubin MA, Getz G, Berger AJ, Ramaswamy S, Beroukhim R, Milner DA, Granter SR, Du J, Lee C, Wagner SN, Li C, Golub TR, Rimm DL, Meyerson ML, Fisher DE and Sellers WR: Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. Nature 436(7047): 117-122, 2005.
98. Wellbrock C, Rana S, Paterson H, Pickersgill H, Brummelkamp T and Marais R: Oncogenic BRAF regulates melanoma proliferation through the lineage specific factor MITF. PLoS One 3(7): e2734, 2008.
99. Yokoyama S, Feige E, Poling LL, Levy C, Widlund HR, Khaled M, Kung AL and Fisher DE: Pharmacologic suppression of MITF expression via HDAC inhibitors in the melanocyte lineage. Pigment Cell Melanoma Res 21(4): 457-463, 2008.
100. Caramuta S, Egyházi S, Rodolfo M, Witten D, Hansson J, Larsson C and Lui WO: MicroRNA expression profiles associated with mutational status and survival in malignant melanoma. J Invest Dermatol 130(8): 2062-2070, 2010.
101. Igoucheva O and Alexeev V: MicroRNA-dependent regulation of cKit in cutaneous melanoma. Biochem Biophys Res Commun 379(3): 790-794, 2009.
102. Yan D, Dong XD, Chen X, Yao S, Wang L, Wang J, Wang C, Hu DN, Qu J and Tu L: Role of microRNA-182 in posterior uveal melanoma: Regulation of tumor development through MITF, BCL2 and cyclin D2. PLoS One 7(7): e40967, 2012.
103. Haflidadóttir BS, Bergsteinsdóttir K, Praetorius C and Steingrímsson E: miR-148 regulates Mitf in melanoma cells. PLoS One 5(7): e11574, 2010.
104. Dar AA, Majid S, de Semir D, Nosrati M, Bezrookove V and Kashani-Sabet M: miRNA-205 suppresses melanoma cell proliferation and induces senescence via regulation of E2F1 protein. J Biol Chem 286(19): 16606-16614, 2011.
105. Dar AA, Majid S, Rittsteuer C, de Semir D, Bezrookove V, Tong S, Nosrati M, Sagebiel R, Miller JR III and Kashani-Sabet M: The role of miR-18b in MDM2-p53 pathway signaling and melanoma progression. J Natl Cancer Inst 105(6): 433-442, 2013.