Multiple molecular pathways in melanomagenesis: Characterization of therapeutic targets

Frontiers in Oncology

Volumn 5, Issue Aug, 2015, Pages

  Palmieri, Giuseppe ^a   Ombra, MariaNeve ^b   Colombino, Maria ^a   Casula, Milena ^a   Sini, MariaCristina ^a   Manca, Antonella ^a   Paliogiannis, Panagiotis ^c   Ascierto, Paolo Antonio ^d   Cossu, Antonio ^c  

^a CNR   (Italy)

^b CNR   (Italy)

^c UNIVERSITY OF SASSARI   (Italy)

^d NATIONAL CANCER INSTITUTE   (Italy)

Author keywords

Alternative therapeutic targets; Melanoma pathogenesis; Molecular melanoma classification; Signal transduction cascades; Targeted therapy resistance

Indexed keywords

AURORA KINASE; B RAF KINASE; CYCLIN DEPENDENT KINASE 4; CYCLIN DEPENDENT KINASE INHIBITOR 2A; DABRAFENIB; METFORMIN; MICROPHTHALMIA ASSOCIATED TRANSCRIPTION FACTOR; MITOGEN ACTIVATED PROTEIN KINASE; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 4,5 BISPHOSPHATE; PROTEIN MDM2; PROTEIN P53; VEMURAFENIB;

AUTOPHAGY; CELL CYCLE PROGRESSION; CELL PROLIFERATION; CELL SURVIVAL; DRUG TARGETING; EPIGENETICS; GENE AMPLIFICATION; GENE MUTATION; GENE SILENCING; HUMAN; MELANOMA; MOLECULARLY TARGETED THERAPY; ONCOGENE RAS; REVIEW; SIGNAL TRANSDUCTION; SYSTEMIC ACQUIRED RESISTANCE; TUMOR GROWTH; TUMOR MICROENVIRONMENT;

EID: 84940989576     PISSN: None     EISSN: 2234943X     Source Type: Journal    
DOI: 10.3389/fonc.2015.00183     Document Type: Review

References (172)

1. Curtin JA, Fridlyand J, Kageshita T, Patel HN, Busam KJ, Kutzner H, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med (2005) 353:2135-47. doi:10.1056/NEJMoa050092.
2. Thompson JF, Scolyer RA, Kefford RF. Cutaneous melanoma. Lancet (2005) 365:687-701. doi:10.1016/S0140-6736(05)70937-5.
3. Balch CM, Gershenwald JE, Soong SJ, Thompson JF, Atkins MB, Byrd DR, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol (2009) 27:6199-206. doi:10.1200/JCO.2009.23.4799.
4. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer (2015) 136:E359-86. doi:10.1002/ijc.29210.
5. Lo JA, Fisher DE. The melanoma revolution: from UV carcinogenesis to a new era in therapeutics. Science (2014) 346:945-9. doi:10.1126/science.1253735.
6. Puzanov I, Amaravadi RK, McArthur GA, Flaherty KT, Chapman PB, Sosman JA, et al. Long-term outcome in BRAF(V600E) melanoma patients treated with vemurafenib: patterns of disease progression and clinical management of limited progression. Eur J Cancer (2015) 51:1435-43. doi:10.1016/j.ejca.2015.04.010.
7. Long GV, Stroyakovsky DL, Gogas H, Levchenko E, de Braud F, Larkin JMG, et al. Overall survival in COMBI-d, a randomized, double-blinded, phase III study comparing the combination of dabrafenib and trametinib with dabrafenib and placebo as first-line therapy in patients (pts) with unresectable or metastatic BRAF V600E/K mutation-positive cutaneous melanoma. J Clin Oncol (2015) 33(Suppl):abstr102.
8. Simeone E, Grimaldi AM, Ascierto PA. Anti-PD1 and anti-PD-L1 in the treatment of metastatic melanoma. Melanoma Manag (2015) 2:41-50. doi:10.2217/MMT.14.30.
9. Kamb A, Shattuck-Eidens D, Eeles R, Liu Q, Gruis NA, Ding W, et al. Analysis of the p16 gene (CDKN2) as a candidate for the chromosome 9p melanoma susceptibility locus. Nat Genet (1994) 8:23-6. doi:10.1038/ng0994-22.
10. Gil J, Peters G. Regulation of the INK4b-ARF-INK4a tumour suppressor locus: all for one or one for all. Nat Rev Mol Cell Biol (2006) 7:667-77. doi:10.1038/nrm1987.
11. Meyle KD, Guldberg P. Genetic risk factors for melanoma. Hum Genet (2009) 126:499-510. doi:10.1007/s00439-009-0715-9.
12. Palmieri G, Capone ME, Ascierto ML, Gentilcore G, Stroncek DF, Casula M, et al. Main roads to melanoma. J Transl Med (2009) 7:86. doi:10.1186/1479-5876-7-86.
13. Palmieri G, Casula M, Sini MC, Ascierto PA, Cossu A. Issues affecting molecular staging in the management of patients with melanoma. J Cell Mol Med (2007) 11:1052-68. doi:10.1111/j.1582-4934.2007.00091.x.
14. Smalley KS, Lioni M, Dalla Palma M, Xiao M, Desai B, Egyhazi S, et al. Increased cyclin D1 expression can mediate BRAF inhibitor resistance in BRAF V600E-mutated melanomas. Mol Cancer Ther (2008) 7:2876-83. doi:10.1158/1535-7163.MCT-08-0431.
15. Box NF, Terzian T. The role of p53 in pigmentation, tanning and melanoma. Pigment Cell Melanoma Res (2008) 21:525-33. doi:10.1111/j.1755-148X.2008.00495.x.
16. Giehl K. Oncogenic Ras in tumor progression and metastasis. Biol Chem (2005) 386:193-205. doi:10.1515/BC.2005.025.
17. 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. doi:10.1038/sj.jid.5700026.
18. Wellbrock C, Karasarides M, Marais R. The RAF proteins take centre stage. Nat Rev Mol Cell Biol (2004) 5:875-85. doi:10.1038/nrm1498.
19. Rebocho AP, Marais R. ARAF acts as a scaffold to stabilize BRAF:CRAF heterodimers. Oncogene (2013) 32:3207-12. doi:10.1038/onc.2012.330.
20. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature (2002) 417:949-54. doi:10.1038/nature00766.
21. Pollock PM, Harper UL, Hansen KS, Yudt LM, Stark M, Robbins CM, et al. High frequency of BRAF mutations in nevi. Nat Genet (2003) 33:19-20. doi:10.1038/ng1054.
22. Michaloglou C, Vredeveld LC, Soengas MS, Denoyelle C, Kuilman T, van der Horst CM, et al. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature (2005) 436:720-4. doi:10.1038/nature03890.
23. Patton EE, Widlund HR, Kutok JL, Kopani KR, Amatruda JF, Murphey RD, et al. BRAF mutations are sufficient to promote nevi formation and cooperate with p53 in the genesis of melanoma. Curr Biol (2005) 15:249-54. doi:10.1016/j.cub.2005.01.031.
24. Arcaro A, Guerreiro AS. The phosphoinositide 3-kinase pathway in human cancer: genetic alterations and therapeutic implications. Curr Genomics (2007) 8:271-306. doi:10.2174/138920207782446160.
25. Wellbrock C, Rana S, Paterson H. Oncogenic BRAF regulates melanoma proliferation through the lineage specific factor MITF. PLoS One (2008) 3:2734. doi:10.1371/journal.pone.0002734.
26. Steingrímsson E, Copeland NG, Jenkins NA. Melanocytes and the microphthalmia transcription factor network. Annu Rev Genet (2004) 38:365-411. doi:10.1146/annurev.genet.38.072902.092717.
27. Yajima I, Kumasaka MY, Thang ND, Goto Y, Takeda K, Iida M, et al. Molecular network associated with MITF in skin melanoma development and progression. J Skin Cancer (2011) 2011:730170. doi:10.1155/2011/730170.
28. Garraway LA, Widlund HR, Rubin MA, Getz G, Berger AJ, Ramaswamy S, et al. Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. Nature (2005) 436:117-22. doi:10.1038/nature03664.
29. Hoek KS, Eichhoff OM, Schlegel NC, Döbbeling U, Kobert N, Schaerer L, et al. In vivo switching of human melanoma cells between proliferative and invasive states. Cancer Res (2008) 68:650-6. doi:10.1158/0008-5472.CAN-07-2491.
30. Smalley KS, Sondak VK, Weber JS. c-Kit signaling as the driving oncogenic event in sub-groups of melanomas. histology and histopathology cellular and molecular biology. J Pathol (2009) 29:643-50.
31. Beadling C, Jacobson-Dunlop E, Hodi FS, Le C, Warrick A, Patterson J, et al. KIT gene mutations and copy number in melanoma subtypes. Clin Cancer Res (2008) 14:6821-8. doi:10.1158/1078-0432.CCR-08-0575.
32. Van Raamsdonk CD, Bezrookove V, Green G, Bauer J, Gaugler L, O'Brien JM, et al. Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature (2009) 457:599-602. doi:10.1038/nature07586.
33. Kashani-Sabet M, Range J, Torabian S, Nosrati M, Simko J, Jablons DM, et al. A multi-marker assay to distinguish malignant melanomas from benign nevi. Proc Natl Acad Sci U S A (2009) 106:6268-72. doi:10.1073/pnas.0901185106.
34. Sikora AG, Gelbard A, Davies A, Sano D, Ekmekcioglu S, Kwon J, et al. Targeted inhibition of inducible nitric oxide synthase inhibits growth of human melanoma in vivo and synergizes with chemo-therapy. Clin Cancer Res (2010) 16:1834-44. doi:10.1158/1078-0432.CCR-09-3123.
35. Clague MJ. Met receptor: a moving target. Sci Signal (2011) 4:e40. doi:10.1126/scisignal.2002422.
36. Lee YJ, Kim DH, Lee SH, Kim DW, Nam HS, Cho MK. Expression of the c-Met proteins in malignant skin cancers. Ann Dermatol (2011) 23:33-8. doi:10.5021/ad.2011.23.1.33.
37. Braeuer RR, Zigler M, Villares GJ, Dobroff AS, Bar-Eli M. Transcriptional control of melanoma metastasis: the importance of the tumor microenvironment. Semin Cancer Biol (2011) 21:83-8. doi:10.1016/j.semcancer.2010.12.007.
38. Gajewski TF, Fuertes M, Spaapen R, Zheng Y, Kline J. Molecular profiling to identify relevant immune resistance mechanisms in the tumor microenvironment. Curr Opin Immunol (2011) 23:286-92. doi:10.1016/j.coi.2010.11.013.
39. Smalley KS. Understanding melanoma signaling networks as the basis for molecular targeted therapy. J Invest Dermatol (2010) 130:28-37. doi:10.1038/jid.2009.177.
40. Jang S, Atkins MB. Which drug, and when, for patients with BRAF-mutant melanoma? Lancet Oncol (2013) 14:e60-9. doi:10.1016/S1470-2045(12)70539-9.
41. Lee B, Sandhu S, McArthur G. Cell cycle control as a promising target in melanoma. Curr Opin Oncol (2015) 27:141-50. doi:10.1097/CCO.0000000000000159.
42. Boyle GM, Martyn AC, Parsons PG. Histone deacetylase inhibitors and malignant melanoma. Pigment Cell Res (2005) 18:160-6. doi:10.1111/j.1600-0749.2005.00228.x.
43. Yokoyama S, Feige E, Poling LL, Levy C, Widlund HR, Khaled M, et al. Pharmacologic suppression of MITF expression via HDAC inhibitors in the melanocyte lineage. Pigment Cell Melanoma Res (2008) 21:457-63. doi:10.1111/j.1755-148X.2008.00480.x.
44. Fedorenko IV, Gibney GT, Smalley KS. NRAS mutant melanoma: biological behavior and future strategies for therapeutic management. Oncogene (2013) 32:3009-18. doi:10.1038/onc.2012.453.
45. Greger JG, Eastman SD, Zhang V, Bleam MR, Hughes AM, Smitheman KN, et al. Combinations of BRAF, MEK, and PI3K/mTOR inhibitors overcome acquired resistance to the BRAF inhibitor GSK2118436 dabrafenib, mediated by NRAS or MEK mutations. Mol Cancer Ther (2012) 11:909-20. doi:10.1158/1535-7163.MCT-11-0989.
46. Niessner H, Forschner A, Klumpp B, Honegger JB, Witte M, Bornemann A, et al. Targeting hyperactivation of the AKT survival pathway to overcome therapy resistance of melanoma brain metastases. Cancer Med (2013) 2:76-85. doi:10.1002/cam4.50.
47. Salama AK, Kim KB. MEK inhibition in the treatment of advanced melanoma. Curr Oncol Rep (2013) 15:473-82. doi:10.1007/s11912-013-0336-2.
48. Downward J. Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer (2003) 3:11-22. doi:10.1038/nrc969.
49. Saxena N, Lahiri SS, Hambarde S, Tripathi RP. RAS: target for cancer therapy. Cancer Invest (2008) 26:948-55. doi:10.1080/07357900802087275.
50. Flaherty KT, Hodi FS, Bastian BC. Mutation-driven drug development in melanoma. Curr Opin Oncol (2010) 22:178-83. doi:10.1097/CCO.0b013e32833888ee.
51. Sensi M, Nicolini G, Petti C, Bersani I, Lozupone F, Molla A, et al. Mutually exclusive N-Ras Q61R and BRAF V600E mutations at the single-cell level in the same human melanoma. Oncogene (2006) 25:3357-64. doi:10.1038/sj.onc.1209379.
52. Thomas NE. BRAF somatic mutations in malignant melanoma and melanocytic naevi. Melanoma Res (2006) 16:97-103. doi:10.1097/01.cmr.0000215035.38436.87.
53. Colombino M, Lissia A, Capone M, De Giorgi V, Massi D, Stanganelli I, et al. Heterogeneous distribution of BRAF/NRAS mutations among Italian patients with advanced melanoma. J Transl Med (2013) 11:202. doi:10.1186/1479-5876-11-202.
54. Menzies AM, Haydu LE, Visintin L, Carlino MS, Howle JR, Thompson JF, et al. Distinguishing clinicopathologic features of patients with V600E and V600K BRAF-mutant metastatic melanoma. Clin Cancer Res (2012) 18:3242-9. doi:10.1158/1078-0432.CCR-12-0052.
55. Keith T, Flaherty KT, Hodi FS, Fisher DE. From genes to drugs: targeted strategies for melanoma. Nat Rev Cancer (2012) 12:349-61. doi:10.1038/nrc3218.
56. Ascierto PA, Grimaldi AM, Anderson AC, Bifulco C, Cochran A, Garbe C, et al. Future perspectives in melanoma research: meeting report from the "melanoma bridge", Napoli, December 5th-8th 2013. J Transl Med (2014) 12:277. doi:10.1186/s12967-014-0277-z.
57. Menzies AM, Long GV. Systemic treatment for BRAF-mutant melanoma: where do we go next? Lancet Oncol (2014) 15:e371-81. doi:10.1016/S1470-2045(14)70072-5.
58. Fedorenko IV, Gibney GT, Sondak VK, Smalley KS. Beyond BRAF: where next for melanoma therapy? Br J Cancer (2015) 112:217-26. doi:10.1038/bjc.2014.476.
59. Strickland LR, Pal HC, Elmets CA, Afaq F. Targeting drivers of melanoma with synthetic small molecules and phytochemicals. Cancer Lett (2015) 359:20-35. doi:10.1016/j.canlet.2015.01.016.
60. Akinleye A, Furqan M, Mukhi N, Ravella P, Liu D. MEK and the inhibitors: from bench to bedside. J Hematol Oncol (2013) 6:27. doi:10.1186/1756-8722-6-27.
61. Kim DW, Patel SP. Profile of selumetinib and its potential in the treatment of melanoma. Onco Targets Ther (2014) 7:1631-9. doi:10.2147/OTT.S51596.
62. King JW, Nathan PD. Role of the MEK inhibitor trametinib in the treatment of metastatic melanoma. Future Oncol (2014) 10:1559-70. doi:10.2217/fon.14.89.
63. Bucheit AD, Syklawer E, Jakob JA, Bassett RL Jr, Curry JL, Gershenwald JE, et al. Clinical characteristics and outcomes with specific BRAF and NRAS mutations in patients with metastatic melanoma. Cancer (2013) 119:3821-9. doi:10.1002/cncr.28306.
64. Jaiswal BS, Janakiraman V, Kljavin NM, Eastham-Anderson J, Cupp JE, Liang Y, et al. Combined targeting of BRAF and CRAF or BRAF and PI3K effector pathways is required for efficacy in NRAS mutant tumors. PLoS One (2009) 4:e5717. doi:10.1371/journal.pone.0005717.
65. Lin J, Takata M, Murata H, Goto Y, Kido K, Ferrone S, et al. Polyclonality of BRAF mutations in acquired melanocytic nevi. J Natl Cancer Inst (2009) 101:1423-7. doi:10.1093/jnci/djp309.
66. Colombino M, Capone M, Lissia A, Cossu A, Rubino C, De Giorgi V, et al. BRAF/NRAS mutation frequencies among primary tumors and metastases in patients with melanoma. J Clin Oncol (2012) 30:2522-9. doi:10.1200/JCO.2011.41.2452.
67. Yancovitz M, Litterman A, Yoon J, Ng E, Shapiro RL, Berman RS, et al. Intra-and inter-tumor heterogeneity of BRAF(V600E))mutations in primary and metastatic melanoma. PLoS One (2012) 7:e29336. doi:10.1371/journal.pone.0029336.
68. Colombino M, Sini M, Lissia A, De Giorgi V, Stanganelli I, Ayala F, et al. Discrepant alterations in main candidate genes among multiple primary melanomas. J Transl Med (2014) 12:117. doi:10.1186/1479-5876-12-117.
69. Larkin J, Ascierto PA, Dréno B, Atkinson V, Liszkay G, Maio M, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med (2014) 371:1867-76. doi:10.1056/NEJMoa1408868.
70. Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med (2014) 371:1877-88. doi:10.1056/NEJMoa1406037.
71. Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med (2015) 372:30-9. doi:10.1056/NEJMoa1412690.
72. Diaz LA Jr, Williams RT, Wu J, Kinde I, Hecht JR, Berlin J, et al. The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature (2012) 486:537-40. doi:10.1038/nature11219.
73. Doebele RC, Pilling AB, Aisner DL, Kutateladze TG, Le AT, Weickhardt AJ, et al. Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res (2012) 18:1472-82. doi:10.1158/1078-0432.CCR-11-2906.
74. Misale S, Yaeger R, Hobor S, Scala E, Janakiraman M, Liska D, et al. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature (2012) 486:532-6. doi:10.1038/nature11156.
75. Van Allen EM, Wagle N, Sucker A, Treacy DJ, Johannessen CM, Goetz EM, et al. The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma. Cancer Discov (2014) 4:94-109. doi:10.1158/2159-8290.CD-13-0617.
76. Paraiso KH, Xiang Y, Rebecca VW, Abel EV, Chen YA, Munko AC, et al. PTEN loss confers BRAF inhibitor resistance to melanoma cells through the suppression of BIM expression. Cancer Res (2011) 71:2750-60. doi:10.1158/0008-5472.CAN-10-2954.
77. Lee EK, Lian Z, D'Andrea K, Letrero R, Sheng W, Liu S, et al. The FBXO4 tumor suppressor functions as a barrier to BrafV600E-dependent metastatic melanoma. Mol Cell Biol (2013) 33:4422-33. doi:10.1128/MCB.00706-13.
78. Whittaker SR, Theurillat JP, Van Allen E, Wagle N, Hsiao J, Cowley GS, et al. A genome-scale RNA interference screen implicates NF1 loss in resistance to RAF inhibition. Cancer Discov (2013) 3:350-62. doi:10.1158/2159-8290.CD-12-0470.
79. Chen J, Shen Q, Labow M, Gaither LA. Protein kinase D3 sensitizes RAF inhibitor RAF265 in melanoma cells by preventing reactivation of MAPK signaling. Cancer Res (2011) 71:4280-91. doi:10.1158/0008-5472.CAN-10-3761.
80. Carlino MS, Todd JR, Gowrishankar K, Mijatov B, Pupo GM, Fung C, et al. Differential activity of MEK and ERK inhibitors in BRAF inhibitor resistant melanoma. Mol Oncol (2014) 8:544-54. doi:10.1016/j.molonc.2014.01.003.
81. Nissan MH, Pratilas CA, Jones AM, Ramirez R, Won H, Liu C, et al. Loss of NF1 in cutaneous melanoma is associated with RAS activation and MEK dependence. Cancer Res (2014) 74:2340-50. doi:10.1158/0008-5472.CAN-13-2625.
82. Poulikakos PI, Persaud Y, Janakiraman M, Kong X, Ng C, Moriceau G, et al. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature (2011) 480:387-90. doi:10.1038/nature10662.
83. Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H, et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature (2010) 468:973-7. doi:10.1038/nature09626.
84. Miao B, Ji Z, Tan L, Taylor M, Zhang J, Choi HG, et al. EPHA2 is a mediator of vemurafenib resistance and a novel therapeutic target in melanoma. Cancer Discov (2015) 5:274-87. doi:10.1158/2159-8290.CD-14-0295.
85. Paraiso KH, Das Thakur M, Fang B, Koomen JM, Fedorenko IV, John JK, et al. Ligand-independent EPHA2 signaling drives the adoption of a targeted therapy-mediated metastatic melanoma phenotype. Cancer Discov (2015) 5:264-73. doi:10.1158/2159-8290.CD-14-0293.
86. Straussman R, Morikawa T, Shee K, Barzily-Rokni M, Qian ZR, Du J, et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature (2012) 487:500-4. doi:10.1038/nature11183.
87. Carlino MS, Gowrishankar K, Saunders CA, Pupo GM, Snoyman S, Zhang XD, et al. Antiproliferative effects of continued mitogen-activated protein kinase pathway inhibition following acquired resistance to BRAF and/or MEK inhibition in melanoma. Mol Cancer Ther (2013) 12:1332-42. doi:10.1158/1535-7163.MCT-13-0011.
88. Villanueva J, Vultur A, Lee JT, Somasundaram R, Fukunaga-Kalabis M, Cipolla AK, et al. Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K. Cancer Cell (2010) 18:683-95. doi:10.1016/j.ccr.2010.11.023.
89. Liu F, Cao J, Wu J, Sullivan K, Shen J, Ryu B, et al. Stat3-targeted therapies overcome the acquired resistance to vemurafenib in melanomas. J Invest Dermatol (2013) 133:2041-9. doi:10.1038/jid.2013.32.
90. Vultur A, Villanueva J, Krepler C, Rajan G, Chen Q, Xiao M, et al. MEK inhibition affects STAT3 signaling and invasion in human melanoma cell lines. Oncogene (2014) 33:1850-61. doi:10.1038/onc.2013.131.
91. 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:djt435. doi:10.1093/jnci/djt435.
92. Yadav V, Zhang X, Liu J, Estrem S, Li S, Gong XQ, et al. Reactivation of mitogen-activated protein kinase (MAPK) pathway by FGF receptor 3 (FGFR3)/Ras mediates resistance to vemurafenib in human B-RAF V600E mutant melanoma. J Biol Chem (2012) 287:28087-98. doi:10.1074/jbc.M112.377218.
93. Curry JL, Torres-Cabala CA, Kim KB, Tetzlaff MT, Duvic M, Tsai KY, et al. Dermatologic toxicities to targeted cancer therapy: shared clinical and histologic adverse skin reactions. Int J Dermatol (2014) 53:376-84. doi:10.1111/ijd.12205.
94. Hatzivassiliou G, Song K, Yen I, Brandhuber BJ, Anderson DJ, Alvarado R, et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature (2010) 464:431-5. doi:10.1038/nature08833.
95. Heidorn SJ, Milagre C, Whittaker S, Nourry A, Niculescu-Duvas I, Dhomen N, et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell (2010) 140:209-21. doi:10.1016/j.cell.2009.12.040.
96. Poulikakos PI, Zhang C, Bollag G, Shokat KM, Rosen N. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature (2010) 464:427-30. doi:10.1038/nature08902.
97. Mandalà M, Voit C. Targeting BRAF in melanoma: biological and clinical challenges. Crit Rev Oncol Hematol (2013) 87:239-55. doi:10.1016/j.critrevonc.2013.01.003.
98. Romano E, Pradervand S, Paillusson A, Weber J, Harshman K, Muehlethaler K, et al. Identification of multiple mechanisms of resistance to vemurafenib in a patient with BRAFV600E-mutated cutaneous melanoma successfully rechallenged after progression. Clin Cancer Res (2013) 19:5749-57. doi:10.1158/1078-0432.CCR-13-0661.
99. Corcoran RB, Dias-Santagata D, Bergethon K, Iafrate AJ, Settleman J, Engelman JA. BRAF gene amplification can promote acquired resistance to MEK inhibitors in cancer cells harboring the BRAF V600E mutation. Sci Signal (2010) 3:ra84. doi:10.1126/scisignal.2001148.
100. Dhas Thakur M, Salangsang F, Landman AS, Sellers WR, Pryer NK, Levesque MP, et al. Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance. Nature (2013) 494:251-5. doi:10.1038/nature11814.
101. Wilson TR, Fridlyand J, Yan Y, Penuel E, Burton L, Chan E, et al. Widespread potential for growth-factor driven resistance to anticancer kinase inhibitors. Nature (2012) 487:505-9. doi:10.1038/nature11249.
102. Ucar DA, Kurenova E, Garrett TJ, Cance WG, Nyberg C, Cox A, et al. Disruption of the protein interaction between FAK and IGF-1R inhibits melanoma tumor growth. Cell Cycle (2012) 11:3250-9. doi:10.4161/cc.21611.
103. Hartsough EJ, Aplin AE. A STATement on vemurafenib-resistant melanoma. J Invest Dermatol (2013) 133:1928-9. doi:10.1038/jid.2013.136.
104. Becker TM, Boyd SC, Mijatov B, Gowrishankar K, Snoyman S, Pupo GM, et al. Mutant B-RAF-Mcl-1 survival signaling depends on the STAT3 transcription factor. Oncogene (2014) 33:1158-66. doi:10.1038/onc.2013.45.
105. Dai B, Meng J, Peyton M, Girard L, Bornmann WG, Ji L, et al. STAT3 mediates resistance to MEK inhibitor through microRNA miR-17. Cancer Res (2011) 71:3658-68. doi:10.1158/0008-5472.CAN-10-3647.
106. Johannessen CM, Boehm JS, Kim SY, Thomas SR, Wardwell L, Johnson LA, et al. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature (2010) 468:968-72. doi:10.1038/nature09627.
107. Hodis E, Watson IR, Kryukov GV, Arold ST, Imielinski M, Theurillat JP, et al. A landscape of driver mutations in melanoma. Cell (2012) 150:251-63. doi:10.1016/j.cell.2012.06.024.
108. Deng W, Gopal YN, Scott A, Chen G, Woodman SE, Davies MA. Role and therapeutic potential of PI3K-mTOR signaling in de novo resistance to BRAF inhibition. Pigment Cell Melanoma Res (2012) 25:248-58. doi:10.1111/j.1755-148X.2011.00950.x.
109. Shi H, Hugo W, Kong X, Hong A, Koya RC, Moriceau G, et al. Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy. Cancer Discov (2014) 4:80-93. doi:10.1158/2159-8290.CD-13-0642.
110. Byers LA, Diao L, Wang J, Saintigny P, Girard L, Peyton M, et al. An epithelial-mesenchymal transition gene signature predicts resistance to EGFR and PI3K inhibitors and identifies Axl as a therapeutic target for overcoming EGFR inhibitor resistance. Clin Cancer Res (2013) 19:279-90. doi:10.1158/1078-0432.CCR-12-1558.
111. Kemper K, de Goeje PL, Peeper DS, van Amerongen R. Phenotype switching: tumor cell plasticity as a resistance mechanism and target for therapy. Cancer Res (2014) 74:5937-41. doi:10.1158/0008-5472.CAN-14-1174.
112. Konieczkowski DJ, Johannessen CM, Abudayyeh O, Kim JW, Cooper ZA, Piris A, et al. A melanoma cell state distinction influences sensitivity to MAPK pathway inhibitors. Cancer Discov (2014) 4:816-27. doi:10.1158/2159-8290.CD-13-0424.
113. Levy C, Khaled M, Fisher DE. MITF: master regulator of melanocyte development and melanoma oncogene. Trends Mol Med (2006) 12:406-14. doi:10.1016/j.molmed.2006.07.008.
114. Du J, Widlund HR, Horstmann MA, Ramaswamy S, Ross K, Huber WE, et al. Critical role of CDK2 for melanoma growth linked to its melanocyte-specific transcriptional regulation by MITF. Cancer Cell (2004) 6:565-76. doi:10.1016/j.ccr.2004.10.014.
115. Zipser MC, Eichhoff OM, Widmer DS, Schlegel NC, Schoenewolf NL, Stuart D, et al. A proliferative melanoma cell phenotype is responsive to RAF/MEK inhibition independent of BRAF mutation status. Pigment Cell Melanoma Res (2011) 24:326-33. doi:10.1111/j.1755-148X.2010.00823.x.
116. Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med (2012) 366:883-92. doi:10.1056/NEJMoa1113205.
117. Neelakantan D, Drasin DJ, Ford HL. Intratumoral heterogeneity: clonal cooperation in epithelial-to-mesenchymal transition and metastasis. Cell Adh Migr (2014) 16:0. doi:10.4161/19336918.2014.972761.
118. Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell (2008) 132:27-42. doi:10.1016/j.cell.2007.12.018.
119. Klionsky DJ. Autophagy. Curr Biol (2005) 15:R282-3. doi:10.1016/j.cub.2005.04.013.
120. Xie Z, Klionsky DJ. Autophagosome formation: core machinery and adaptations. Nat Cell Biol (2007) 9:1102-9. doi:10.1038/ncb1007-1102.
121. Mehrpour M, Esclatine A, Beau I, Codogno P. Overview of macroautophagy regulation in mammalian cells. Cell Res (2010) 20:748-62. doi:10.1038/cr.2010.82.
122. Maiuri MC, Tasdemir E, Criollo A, Morselli E, Vicencio JM, Carnuccio R, et al. Control of autophagy by oncogenes and tumor suppressor genes. Cell Death Differ (2009) 16:87-93. doi:10.1038/cdd.2008.131.
123. Woodard J, Platanias LC. AMP-activated kinase (AMPK)-generated signals in malignant melanoma cell growth and survival. Biochem Biophys Res Commun (2010) 398:135-9. doi:10.1016/j.bbrc.2010.06.052.
124. Pollak M. Metformin and other biguanides in oncology: advancing the research agenda. Cancer Prev Res (Phila) (2010) 3:1060-5. doi:10.1158/1940-6207.CAPR-10-0175.
125. Janjetovic K, Harhaji-Trajkovic L, Misirkic-Marjanovic M, Vucicevic L, Stevanovic D, Zogovic N, et al. In vitro and in vivo anti-melanoma action of metformin. Eur J Pharmacol (2011) 668:373-82. doi:10.1016/j.ejphar.2011.07.004.
126. El-Mir MY, Nogueira V, Fontaine E, Averet N, Rigoulet M, Leverve X. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem (2000) 275:223-8. doi:10.1074/jbc.275.1.223.
127. Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J (2000) 348:607-14. doi:10.1042/0264-6021:3480607.
128. Shaw RJ, Kosmatka M, Bardeesy N, Hurley RL, Witters LA, Depinho RA, et al. The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc Natl Acad Sci U S A (2004) 101:3329-35. doi:10.1073/pnas.0308061100.
129. Luo Z, Zang M, Guo W. AMPK as a metabolic tumor suppressor: control of metabolism and cell growth. Future Oncol (2010) 6:457-70. doi:10.2217/fon.09.174.
130. Buzzai M, Jones RG, Amaravadi RK, Lum JJ, Deberardinis RJ, Zhao F, et al. Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res (2007) 67:6745-52. doi:10.1158/0008-5472.CAN-06-4447.
131. Ben Sahra I, Laurent K, Giuliano S, Larbret F, Ponzio G, Gounon P, et al. Targeting cancer cell metabolism: the combination of metformin and 2-deoxyglucose induces p53-dependent apoptosis in prostate cancer cells. Cancer Res (2010) 70:2465-75. doi:10.1158/0008-5472.CAN-09-2782.
132. Tomic T, Botton T, Cerezo M, Robert G, Luciano F, Puissant A, et al. Metformin inhibits melanoma development through autophagy and apoptosis mechanisms. Cell Death Dis (2011) 2:e199. doi:10.1038/cddis.2011.86.
133. Petti C, Vegetti C, Molla A, Bersani I, Cleris L, Mustard KJ, et al. AMPK activators inhibit the proliferation of human melanomas bearing the activated MAPK pathway. Melanoma Res (2012) 22:341-50. doi:10.1097/CMR.0b013e3283544929.
134. Yuan P, Ito K, Perez-Lorenzo R, Del Guzzo C, Lee JH, Shen CH, et al. Phenformin enhances the therapeutic benefit of BRAF(V600E) inhibition in melanoma. Proc Natl Acad Sci U S A (2013) 110:18226-31. doi:10.1073/pnas.1317577110.
135. Niehr F, von Euw E, Attar N, Guo D, Matsunaga D, Sazegar H, et al. Combination therapy with vemurafenib (PLX4032/RG7204) and metformin in melanoma cell lines with distinct driver mutations. J Transl Med (2011) 9:76. doi:10.1186/1479-5876-9-76.
136. Roesch A, Vultur A, Bogeski I, Wang H, Zimmermann KM, Speicher D, et al. Overcoming intrinsic multidrug resistance in melanoma by blocking the mitochondrial respiratory chain of slow-cycling JARID1B(high) cells. Cancer Cell (2013) 23:811-25. doi:10.1016/j.ccr.2013.05.003.
137. Ohanna M, Cheli Y, Bonet C, Bonazzi VF, Allegra M, Giuliano S, et al. Secretome from senescent melanoma engages the STAT3 pathway to favor reprogramming of naive melanoma towards a tumor-initiating cell phenotype. Oncotarget (2013) 4:2212-24.
138. Hoek KS, Goding CR. Cancer stem cells versus phenotype-switching in melanoma. Pigment Cell Melanoma Res (2010) 23:746-59. doi:10.1111/j.1755-148X.2010.00757.x.
139. Cerezo M, Tomic T, Ballotti R, Rocchi S. Is it time to test biguanide metformin in the treatment of melanoma? Pigment Cell Melanoma Res (2015) 28:8-20. doi:10.1111/pcmr.12267.
140. Frank A, David V, Aurelie TR, Florent G, William H, Philippe B. Regulation of MMPs during melanoma progression: from genetic to epigenetic. Anticancer Agents Med Chem (2012) 12:773-82. doi:10.2174/187152012802650228.
141. Weinhold N, Jacobsen A, Schultz N, Sander C, Lee W. Genome-wide analysis of noncoding regulatory mutations in cancer. Nat Genet (2014) 46:1160-5. doi:10.1038/ng.3101.
142. Horn S, Figl A, Rachakonda PS, Fischer C, Sucker A, Gast A, et al. TERT promoter mutations in familial and sporadic melanoma. Science (2013) 339:959-61. doi:10.1126/science.1230062.
143. Huang FW, Hodis E, Xu MJ, Kryukov GV, Chin L, Garraway LA. Highly recurrent TERT promoter mutations in human melanoma. Science (2013) 339:957-9. doi:10.1126/science.1229259.
144. Carbone M, Ferris LK, Baumann F, Napolitano A, Lum CA, Flores EG, et al. BAP1 cancer syndrome: malignant mesothelioma, uveal and cutaneous melanoma, and MBAITs. J Transl Med (2012) 10:179. doi:10.1186/1479-5876-10-179.
145. Shi J, Yang XR, Ballew B, Rotunno M, Calista D, Fargnoli MC, et al. Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma. Nat Genet (2014) 46:482-6. doi:10.1038/ng.2941.
146. Loayza D, De Lange T. POT1 as a terminal transducer of TRF1 telomere length control. Nature (2003) 423:1013-8. doi:10.1038/nature01688.
147. Palm W, de Lange T. How shelterin protects mammalian telomeres. Annu Rev Genet (2008) 42:301-34. doi:10.1146/annurev.genet.41.110306.130350.
148. Robles-Espinoza CD, Harland M, Ramsay AJ, Aoude LG, Quesada V, Ding Z, et al. POT1 loss-of-function variants predispose to familial melanoma. Nat Genet (2014) 46:478-81. doi:10.1038/ng.2947.
149. Sarris M, Nikolaou K, Talianidis I. Context-specific regulation of cancer epigenomes by histone and transcription factor methylation. Oncogene (2012) 33:1207-17. doi:10.1038/onc.2013.87.
150. Mehrotra A, Mehta G, Aras S, Trivedi A, de la Serna IL. SWI/SNF chromatin remodeling enzymes in melanocyte differentiation and melanoma. Crit Rev Eukaryot Gene Expr (2014) 24:151-61. doi:10.1615/CritRevEukaryotGeneExpr.2014007882.
151. Kuźbicki L, Lange D, Straczyńska-Niemiec A, Chwirot BW. JARID1B expression in human melanoma and benign melanocytic skin lesions. Melanoma Res (2013) 23:8-12. doi:10.1097/CMR.0b013e32835d5d6f.
152. Chang X, Sun Y, Han S, Zhu W, Zhang H, Lian S. miR-203 inhibits melanoma invasive and proliferative abilities by targeting the polycomb group gene BMI1. Biochem Biophys Res Commun (2015) 456:361-6. doi:10.1016/j.bbrc.2014.11.087.
153. Tiffen J, Gallagher SJ, Hersey P. EZH2: an emerging role in melanoma biology and strategies for targeted therapy. Pigment Cell Melanoma Res (2015) 28:21-30. doi:10.1111/pcmr.12280.
154. van den Hurk K, Niessen HE, Veeck J, van den Oord JJ, van Steensel MA, Zur Hausen A, et al. Genetics and epigenetics of cutaneous malignant melanoma: a concert out of tune. Biochim Biophys Acta (2012) 1826:89-102. doi:10.1016/j.bbcan.2012.03.011.
155. Greenberg ES, Chong KK, Huynh KT, Tanaka R, Hoon DS. Epigenetic biomarkers in skin cancer. Cancer Lett (2014) 342:170-7. doi:10.1016/j.canlet.2012.01.020.
156. Xia C, Leon-Ferre R, Laux D, Deutsch J, Smith BJ, Frees M, et al. Treatment of resistant metastatic melanoma using sequential epigenetic therapy (decitabine and panobinostat) combined with chemotherapy (temozolomide). Cancer Chemother Pharmacol (2014) 74:691-7. doi:10.1007/s00280-014-2501-1.
157. Griewank KG, Ugurel S, Schadendorf D, Paschen A. New developments in biomarkers for melanoma. Curr Opin Oncol (2013) 25:145-51. doi:10.1097/CCO.0b013e32835dafdf.
158. La Porta CA. Melanoma and epigenetic treatment: past and future. Anticancer Agents Med Chem (2012) 12:202-9. doi:10.2174/187152012800228760.
159. Geutjes EJ, Bajpe PK, Bernards R. Targeting the epigenome for treatment of cancer. Oncogene (2012) 31:3827-44. doi:10.1038/onc.2011.552.
160. Vader G, Lens SM. The aurora kinase family in cell division and cancer. Biochim Biophys Acta (2008) 1786:60-72. doi:10.1016/j.bbcan.2008.07.003.
161. Mahen R, Venkitaraman AR. Pattern formation in centrosome assembly. Curr Opin Cell Biol (2012) 24:14-23. doi:10.1016/j.ceb.2011.12.012.
162. Lens SM, Voest EE, Medema RH. Shared and separate functions of polo-like kinases and aurora kinases in cancer. Nat Rev Cancer (2010) 10:825-41. doi:10.1038/nrc2964.
163. Nikonova AS, Astsaturov I, Serebriiskii IG, Dunbrack RL Jr, Golemis EA. Aurora A kinase (AURKA) in normal and pathological cell division. Cell Mol Life Sci (2013) 70:661-87. doi:10.1007/s00018-012-1073-7.
164. Lim KH, Brady DC, Kashatus DF, Ancrile BB, Der CJ, Cox AD, et al. Aurora-A phosphorylates, activates, and relocalizes the small GTPase RalA. Mol Cell Biol (2010) 30:508-23. doi:10.1128/MCB.00916-08.
165. Zeng WF, Navaratne K, Prayson RA, Weil RJ. Aurora B expression correlates with aggressive behaviour in glioblastoma multiforme. J Clin Pathol (2007) 60:218-21. doi:10.1136/jcp.2006.036806.
166. Katayama H, Sasai K, Kawai H, Yuan ZM, Bondaruk J, Suzuki F, et al. Phosphorylation by aurora kinase A induces Mdm2-mediated destabilization and inhibition of p53. Nat Genet (2004) 36:55-62. doi:10.1038/ng1279.
167. Caputo E, Miceli R, Motti ML, Taté R, Fratangelo F, Botti G, et al. AurkA inhibitors enhance the effects of B-RAF and MEK inhibitors in melanoma treatment. J Transl Med (2014) 12:216. doi:10.1186/s12967-014-0216-z.
168. Siroy AE, Boland GM, Milton DR, Roszik J, Frankian S, Malke J, et al. Beyond BRAF(V600): clinical mutation panel testing by next-generation sequencing in advanced melanoma. J Invest Dermatol (2015) 135:508-15. doi:10.1038/jid.2014.366.
169. Palmieri G, Colombino M, Sini MC, Manca A, Ascierto PA, Cossu M. Resistance to targeted therapies in melanoma: new insights. EMJ Dermatol (2013) 1:24-37.
170. Hu-Lieskovan S, Robert L, Homet Moreno B, Ribas A. Combining targeted therapy with immunotherapy in BRAF-mutant melanoma: promise and challenges. J Clin Oncol (2014) 32:2248-54. doi:10.1200/JCO.2013.52.1377.
171. Mahoney KM, Freeman GJ, McDermott DF. The next immune-checkpoint inhibitors: PD-1/PD-L1 blockade in melanoma. Clin Ther (2015) 37(4):764-82. doi:10.1016/j.clinthera.2015.02.018.
172. Kunz M. Oncogenes in melanoma: an update. Eur J Cell Biol (2014) 93:1-10. doi:10.1016/j.ejcb.2013.12.002.