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Targeted therapy for melanoma: rational combinatorial approaches

Oncogene volume 33, pages 1–9 (2014)Cite this article

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Abstract

The treatment of melanoma, the most aggressive form of skin cancer, is being revolutionized by the development of personalized targeted therapy approaches. Mutant-selective BRAF inhibitors and MEK inhibitors have demonstrated impressive clinical results in molecularly selected patients. However, emerging understanding of the molecular heterogeneity of this disease and the identification of multiple mechanisms of resistance to targeted therapies strongly support the rationale for combinatorial approaches. In this review, we will discuss the preclinical and clinical studies that are testing leading hypotheses and emerging combinatorial strategies for the future.

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References

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

    Article  CAS  Google Scholar 

  2. 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: 949–954.

    Article  CAS  Google Scholar 

  3. Hocker T, Tsao H . Ultraviolet radiation and melanoma: a systematic review and analysis of reported sequence variants. Hum Mutat 2007; 28: 578–588.

    Article  CAS  Google Scholar 

  4. Krauthammer M, Kong Y, Ha BH, Evans P, Bacchiocchi A, McCusker JP et al. Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma. Nat Genet 2012; 44: 1006–1014.

    Article  CAS  Google Scholar 

  5. Hodis E, Watson Ian R, Kryukov Gregory V, Arold Stefan T, Imielinski M, Theurillat J-P et al. A landscape of driver mutations in melanoma. Cell 2012; 150: 251–263.

    Article  CAS  Google Scholar 

  6. Curtin JA, Busam K, Pinkel D, Bastian BC . Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol 2006; 24: 4340–4346.

    Article  CAS  Google Scholar 

  7. Van Raamsdonk CD, Griewank KG, Crosby MB, Garrido MC, Vemula S, Wiesner T et al. Mutations in GNA11 in uveal melanoma. N Engl J Med 2010; 363: 2191–2199.

    Article  CAS  Google Scholar 

  8. 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.

    Article  CAS  Google Scholar 

  9. Onken MD, Worley LA, Long MD, Duan S, Council ML, Bowcock AM et al. Oncogenic mutations in GNAQ occur early in uveal melanoma. Invest Ophthalmol Vis Sci 2008; 49: 5230–5234.

    Article  Google Scholar 

  10. Harbour JW, Onken MD, Roberson EDO, Duan S, Cao L, Worley LA et al. Frequent mutation of BAP1 in metastasizing uveal melanomas. Science 2010; 330: 1410–1413.

    Article  CAS  Google Scholar 

  11. Devitt B, Liu W, Salemi R, Wolfe R, Kelly J, Tzen C-Y et al. Clinical outcome and pathological features associated with NRAS mutation in cutaneous melanoma. Pigment Cell Mel Res 2011; 24: 666–672.

    Article  CAS  Google Scholar 

  12. Long GV, Menzies AM, Nagrial AM, Haydu LE, Hamilton AL, Mann GJ et al. Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J. Clin Oncol. 2011; 29: 1239–1246.

    Article  Google Scholar 

  13. Jakob JA, Bassett RL, Ng CS, Curry J, Joseph R, Alvarado G et al. NRAS mutation status is an independent prognostic factor in metastatic melanoma. Cancer 2012; 118: 4014–4023.

    Article  CAS  Google Scholar 

  14. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011; 364: 2507–2516.

    Article  CAS  Google Scholar 

  15. Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 2012; 380: 358–365.

    Article  CAS  Google Scholar 

  16. Bollag G, Hirth P, Tsai J, Zhang J, Ibrahim PN, Cho H et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature 2010; 467: 596–599.

    Article  CAS  Google Scholar 

  17. Sosman JA, Pavlick AC, Schuchter LM, Lewis KD, McArthur GA, Cowey CL et al. Analysis of molecular mechanisms of response and resistance to vemurafenib (vem) in BRAF V600E melanoma. J Clin Oncol 2012; 30 (suppl): 8503.

    Google Scholar 

  18. McArthur GA, Ribas A, Chapman PB, Flaherty KT, Kim KB, Puzanov I et al. Molecular analyses from a phase I trial of vemurafenib to study mechanism of action (MOA) and resistance in repeated biopsies from BRAF mutation-positive metastatic melanoma patients. J Clin Oncol 2011; 29: abstract 8502.

    Article  Google Scholar 

  19. 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: 973–977.

    Article  CAS  Google Scholar 

  20. 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: 683–695.

    Article  CAS  Google Scholar 

  21. 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: 387–390.

    Article  CAS  Google Scholar 

  22. Montagut C, Sharma SV, Shioda T, McDermott U, Ulman M, Ulkus LE et al. Elevated CRAF as a potential mechanism of acquired resistance to BRAF inhibition in melanoma. Cancer Res 2008; 68: 4853–4861.

    Article  CAS  Google Scholar 

  23. Whittaker S, Kirk R, Hayward R, Zambon A, Viros A, Cantarino N et al. Gatekeeper mutations mediate resistance to BRAF-targeted therapies. Sci Transl Med 2010; 2: 35ra41.

    Article  Google Scholar 

  24. Shi H, Moriceau G, Kong X, Lee MK, Lee H, Koya RC et al. Melanoma whole-exome sequencing identifies (V600E)B-RAF amplification-mediated acquired B-RAF inhibitor resistance. Nat Commun 2012; 3: 724.

    Article  Google Scholar 

  25. Poulikakos PI, Rosen N . Mutant BRAF melanomas--dependence and resistance. Cancer Cell 2011; 19: 11–15.

    Article  CAS  Google Scholar 

  26. Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 2012; 367: 107–114.

    Article  CAS  Google Scholar 

  27. Kim KB, Lewis KD, Pavlick AC, Infante JR, Ribas A, Sosman JA et al. A phase II study of the MEK1/MEK2 inhibitor GSK1120212 in metastatic BRAF-V600E or K mutant cutaneous melanoma patients previously treated with or without a BRAF inhibitor. Pigment Cell Mel Res 2011; 24 (Suppl): 1021.

    Google Scholar 

  28. Flaherty KT, Infante JR, Falchook GS, Weber J, Daud A, Hamid O et al. Phase I/II expansion cohort of BRAF inhibitor GSK2118436+MEK inhibitor GSK1120212 in patients with BRAF mutant metastatic melanoma who progressed on a prior BRAF inhibitor. Pigment Cell Mel Res 2011; 24 (Suppl): 1022.

    Google Scholar 

  29. Weber JS, Flaherty KT, Infante JR, Falchook GS, Kefford RF, Daud A et al. Updated safety and efficacy results from a phase I/II study of the oral BRAF inhibitor dabrafenib (GSK2118436) combined with the oral MEK 1/2 inhibitor trametinib (GSK1120212) in patients with BRAFi-naive metastatic melanoma. J Clin Oncol 2012; 30 (Suppl): 8510.

    Google Scholar 

  30. Su F, Viros A, Milagre C, Trunzer K, Bollag G, Spleiss O et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med 2012; 366: 207–215.

    Article  CAS  Google Scholar 

  31. Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 2012; 367: 1694–1703.

    Article  CAS  Google Scholar 

  32. Deng W, Yennu-Nanda VG, Scott A, Chen G, Woodman SE, MA Davies . Role and therapeutic potential of PI3K-mTOR signaling in de novo resistance to BRAF inhibition. Pigment Cell Mel Res 2012; 25: 248–258.

    Article  CAS  Google Scholar 

  33. Gopal YN, Deng W, Woodman SE, Komurov K, Ram P, Smith PD et al. Basal and treatment-induced activation of AKT mediates resistance to cell death by AZD6244 (ARRY-142886) in Braf-mutant human cutaneous melanoma cells. Cancer Res 2010; 70: 8736–8747.

    Article  CAS  Google Scholar 

  34. Shi H, Kong X, Ribas A, Lo RS . Combinatorial treatments that overcome PDGFRβ-driven resistance of melanoma cells to V600EB-RAF inhibition. Cancer Res 2011; 71: 5067–5074.

    Article  CAS  Google Scholar 

  35. 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: 500–504.

    Article  CAS  Google Scholar 

  36. Aguissa-Touré A-H, Li G . Genetic alterations of PTEN in human melanoma. Cell Mol Life Sci 2012; 69: 1475–1491.

    Article  Google Scholar 

  37. 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: 154–160.

    Article  CAS  Google Scholar 

  38. Tsao H, Goel V, Wu H, Yang G, Haluska FG . Genetic interaction between NRAS and BRAF mutations and PTEN//MMAC1 inactivation in melanoma. J Investig Dermatol 2004; 122: 337–341.

    Article  CAS  Google Scholar 

  39. Paraiso KH, Xiang Y, Rebecca VW, Abel EV, Chen A, Munko AC et al. PTEN loss confers BRAF inhibitor resistance to melanoma cells through the suppression of BIM expression. Cancer Res 2011; 71: 2750–2760.

    Article  CAS  Google Scholar 

  40. Xing F, Persaud Y, Pratilas CA, Taylor BS, Janakiraman M, She QB et al. Concurrent loss of the PTEN and RB1 tumor suppressors attenuates RAF dependence in melanomas harboring (V600E)BRAF. Oncogene 2012; 31: 248–258.

    Article  Google Scholar 

  41. Nathanson K, Martin A, Letrero R, D/'Andrea K, O'Day S, Infante JR et al. Tumor genetic analyses of patients with metastatic melanoma treated with the BRAF inhibitor GSK2118436 (GSK436). J Clin Oncol 2011; 29 (Suppl)abstract): 8501.

    Article  Google Scholar 

  42. Rodrik-Outmezguine VS, Chandarlapaty S, Pagano NC, Poulikakos PI, Scaltriti M, Moskatel E et al. mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling. Cancer Dis 2011; 1: 248–259.

    Article  CAS  Google Scholar 

  43. Chandarlapaty S, Sawai A, Scaltriti M, Rodrik-Outmezguine V, Grbovic-Huezo O, Serra V et al. AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. Cancer Cell 2011; 19: 58–71.

    Article  CAS  Google Scholar 

  44. O'Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 2006; 66: 1500–1508.

    Article  CAS  Google Scholar 

  45. Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K 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: 2105.

    Article  CAS  Google Scholar 

  46. Phan GQ, Attia P, Steinberg SM, White DE, Rosenberg SA . Factors associated with response to high-dose interleukin-2 in patients with metastatic melanoma. J Clin Oncol 2001; 19: 3477–3482.

    Article  CAS  Google Scholar 

  47. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363: 711–723.

    Article  CAS  Google Scholar 

  48. Robert C, Thomas L, Bondarenko I, O'Day S, M.D JW, Garbe C et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011; 364: 2517–2526.

    Article  CAS  Google Scholar 

  49. Boni A, Cogdill AP, Dang P, Udayakumar D, Njauw C-NJ, Sloss CM et al. Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function. Cancer Res 2010; 70: 5213–5219.

    Article  CAS  Google Scholar 

  50. Wilmott JS, Long GV, Howle JR, Haydu LE, Sharma RN, Thompson JF et al. Selective BRAF inhibitors induce marked T-cell infiltration into human metastatic melanoma. Clin Cancer Res 2012; 18: 1386–1394.

    Article  CAS  Google Scholar 

  51. Hong DS, Vence L, Falchook G, Radvanyi LG, Liu C, Goodman V et al. BRAF(V600) inhibitor GSK2118436 targeted inhibition of mutant BRAF in cancer patients does not impair overall immune competency. Clin Cancer Res 2012; 18: 2326–2335.

    Article  CAS  Google Scholar 

  52. Ihle NT, Byers LA, Kim ES, Saintigny P, Lee JJ, Blumenschein GR et al. Effect of KRAS oncogene substitutions on protein behavior: implications for signaling and clinical outcome. J Natl Cancer Inst 2012; 104: 228–239.

    Article  CAS  Google Scholar 

  53. Dankort D, Curley DP, Cartlidge RA, Nelson B, Karnezis AN, Damsky WE et al. Braf(V600E) cooperates with Pten loss to induce metastatic melanoma. Nat Genet 2009; 41: 544–552.

    Article  CAS  Google Scholar 

  54. Fecher LA, Amaravadi RK, Flaherty KT . The MAPK pathway in melanoma. Curr Opin Oncol 2008; 20: 183–189.

    Article  CAS  Google Scholar 

  55. Kwong LN, Costello JC, Liu H, Jiang S, Helms TL, Langsdorf AE et al. Oncogenic NRAS signaling differentially regulates survival and proliferation in melanoma. Nat Med 2012; 18: 1503–1510.

    Article  CAS  Google Scholar 

  56. Dumaz N, Hayward R, Martin J, Ogilvie L, Hedley D, Curtin JA et al. In melanoma, RAS mutations are accompanied by switching signaling from BRAF to CRAF and disrupted cyclic AMP signaling. Cancer Res 2006; 66: 9483–9491.

    Article  CAS  Google Scholar 

  57. 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: 209–221.

    Article  CAS  Google Scholar 

  58. 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: 427–430.

    Article  CAS  Google Scholar 

  59. Halaban R, Zhang W, Bacchiocchi A, Cheng E, Parisi F, Ariyan S et al. PLX4032, a selective BRAF(V600E) kinase inhibitor, activates the ERK pathway and enhances cell migration and proliferation of BRAF melanoma cells. Pigment Cell Mel Res 2010; 23: 190–200.

    Article  CAS  Google Scholar 

  60. Bos JL . Ras oncogenes in human cancer: a review. Cancer Res 1989; 49: 4682–4689.

    CAS  Google Scholar 

  61. Falchook GS, Lewis KD, Infante JR, Gordon MS, Vogelzang NJ, Demarini DJ et al. Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial. Lancet Oncol 2012; 13: 782–789.

    Article  CAS  Google Scholar 

  62. Kirkwood JM, Bastholt L, Robert C, Sosman J, Larkin J, Hersey P 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: 555–567.

    Article  CAS  Google Scholar 

  63. Ascierto PA, Berking C, Agarwala SS, Schadendorf D, Herpen CV, Queirolo P et al. Efficacy and safety of oral MEK162 in patients with locally advanced and unresectable or metastatic cutaneous melanoma harboring BRAF V600 or NRAS mutations. J Clin Oncol 2012; 30 (suppl)Abstract): 8511.

  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.

    Article  Google Scholar 

  65. Sharfman WH, Hodi FS, Lawrence DP, Flaherty K, Amaravadi RK, Kim KB et al. Results from the first-in-human (FIH) phase I study of the oral RAF inhibitor RAF265 administered daily to patients with advanced cutaneous melanoma. J Clin Oncol 2011; 29 (Suppl)Abstract 8508.

    Article  Google Scholar 

  66. Wilson MA, Zhao F, Letrero R, D'Andrea K, Rimm D, Kirkwood JM et al. Mutation analysis of melanoma tumor samples from ECOG 2603 clinical trial. In: Research AAoC (ed) AACR Annual Meeting. AACR, Chicago, IL, 2012, p. 5557.

    Google Scholar 

  67. Martinez-Garcia M, Banerji U, Albanell J, Bahleda R, Dolly S, Kraeber-Bodéré F et al. First-in-Human, Phase I dose-escalation study of the safety, pharmacokinetics, and pharmacodynamics of RO5126766, a first-in-class dual MEK/RAF inhibitor in patients with solid tumors. Clin Cancer Res 2012; 18: 4806–4819.

    Article  CAS  Google Scholar 

  68. Rodriguez-Viciana P, Warne PH, Dhand R, Vanhaesebroeck B, Gout I, Fry MJ et al. Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature 1994; 370: 527–532.

    Article  CAS  Google Scholar 

  69. De Luca A, Maiello MR, D'Alessio A, Pergameno M, Normanno N . The RAS/RAF/MEK/ERK and the PI3K/AKT signalling pathways: role in cancer pathogenesis and implications for therapeutic approaches. Expert Opin Ther Targets 2012; 16 (Suppl 2): S17–S27.

    Article  CAS  Google Scholar 

  70. Lasithiotakis KG, Sinnberg TW, Schittek B, Flaherty KT, Kulms D, Maczey E et al. Combined inhibition of MAPK and mTOR signaling inhibits growth, induces cell death, and abrogates invasive growth of melanoma cells. J Invest Dermatol 2008; 128: 2013–2023.

    Article  CAS  Google Scholar 

  71. Bedogni B, Welford SM, Kwan AC, Ranger-Moore J, Saboda K, Powell MB . Inhibition of phosphatidylinositol-3-kinase and mitogen-activated protein kinase kinase 1/2 prevents melanoma development and promotes melanoma regression in the transgenic TPRas mouse model. Mol Cancer Ther 2006; 5: 3071–3077.

    Article  CAS  Google Scholar 

  72. Roberts PJ, Usary JE, Darr DB, Dillon PM, Pfefferle AD, Whittle MC et al. Combined PI3K/mTOR and MEK inhibition provides broad antitumor activity in faithful murine cancer models. Clin Cancer Res 2012; 18: 5290–5303.

    Article  CAS  Google Scholar 

  73. Flaherty KT, Lorusso PM, Demichele A, Abramson VG, Courtney R, Randolph SS et al. Phase I, dose-escalation trial of the oral cyclin-dependent kinase 4/6 inhibitor PD 0332991, administered using a 21-day schedule in patients with advanced cancer. Clin Cancer Res 2012; 18: 568–576.

    Article  CAS  Google Scholar 

  74. Vaughn DJ, Flaherty K, Lal P, Gallagher M, O'Dwyer P, Wilner K et al. Treatment of growing teratoma syndrome. N Engl J Med 2009; 360: 423–424.

    Article  CAS  Google Scholar 

  75. Eustace A, Crown J, Clynes M, O'Donovan N . Preclinical evaluation of dasatinib, a potent Src kinase inhibitor, in melanoma cell lines. J Translational Med 2008; 6: 53.

    Article  Google Scholar 

  76. Homsi J, Cubitt CL, Zhang S, Munster PN, Yu H, Sullivan DM et al. Src activation in melanoma and Src inhibitors as therapeutic agents in melanoma. Melanoma Res 2009; 19: 167–175.

    Article  CAS  Google Scholar 

  77. Algazi AP, Weber JS, Andrews SC, Urbas P, Munster PN, DeConti RC et al. Phase I clinical trial of the Src inhibitor dasatinib with dacarbazine in metastatic melanoma. Br J Cancer 2012; 106: 85–91.

    Article  CAS  Google Scholar 

  78. Ferguson J, Arozarena I, Ehrhardt M, Wellbrock C . Combination of MEK and SRC inhibition suppresses melanoma cell growth and invasion. Oncogene 2012; 32: 86–96.

    Article  Google Scholar 

  79. Mishra PJ, Ha L, Rieker J, Sviderskaya EV, Bennett DC, Oberst MD et al. Dissection of RAS downstream pathways in melanomagenesis: a role for Ral in transformation. Oncogene 2010; 29: 2449–2456.

    Article  CAS  Google Scholar 

  80. Zipfel PA, Brady DC, Kashatus DF, Ancrile BD, Tyler DS, Counter CM . Ral activation promotes melanomagenesis. Oncogene 2010; 29: 4859–4864.

    Article  CAS  Google Scholar 

  81. Chattopadhyay C, Ellerhorst JA, Ekmekcioglu S, Greene VR, Davies MA, Grimm EA . Association of activated c-Met with NRAS-mutated human melanomas. Int J Cancer 2012; 131: E56–E65.

    Article  CAS  Google Scholar 

  82. Means-Powell JA, Adjei AA, Puzanov I, Dy GK, Goff LW, Ma WW et al. Safety and efficacy of MEK inhibitor tivantinib (ARQ197) combined with sorafenib in patients (pts) with NRAS wild-type or mutant melanoma from a phase I study. J Clin Oncol 2012; 30 (Suppl)Abstract 8519.

  83. Colomba A, Giuriato S, Dejean E, Thornber K, Delsol G, Tronchere H et al. Inhibition of Rac controls NPM-ALK-dependent lymphoma development and dissemination. Blood Cancer J 2011; 1: e21.

    Article  CAS  Google Scholar 

  84. Wilmott JS, Tembe V, Howle JR, Sharma R, Thompson JF, Rizos H et al. Intratumoral molecular heterogeneity in a BRAF-mutant, BRAF inhibitor-resistant melanoma: a case illustrating the challenges for personalized medicine. Mol Cancer Ther 2012; 11: 2704–2708.

    Article  CAS  Google Scholar 

  85. Lai F, Jin L, Gallagher S, Mijatov B, Zhang XD, Hersey P . Histone deacetylases (HDACs) as mediators of resistance to apoptosis in melanoma and as targets for combination therapy with selective BRAF inhibitors. In: Keiran SMS (ed) Advances in Pharmacology vol. 65. Academic Press, 2012, pp 27–43.

    Google Scholar 

  86. Paraiso KHT, Haarberg E, Wood E, Rebecca VW, Chen YA, Xiang Y et al. The heat shock protein-90 inhibitor XL888 overcomes BRAF inhibitor resistance mediated through diverse mechanisms. Clin Cancer Res 2012; 19: 2502–2514.

    Article  Google Scholar 

  87. Woodman SE, Davies MA . Targeting KIT in melanoma: a paradigm of molecular medicine and targeted therapeutics. Biochem Pharmacol 2010; 80: 568–574.

    Article  CAS  Google Scholar 

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Acknowledgements

MAD is supported by funding from the NIH/NCI (1R01CA154710-01), the Cancer Prevention Research Institute of Texas, the American Society of Clinical Oncology, The MD Anderson SPORE in Melanoma (P50 CA093459-06) and the Melanoma Research Alliance. LK is supported by a Postdoctoral Fellowship from the American Cancer Society (117842-PF-09-261-TBG).

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  1. Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    L N Kwong

  2. Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    M A Davies

  3. Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    M A Davies

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Correspondence to M A Davies.

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MAD has served on advisory boards for GlaxoSmithKline, Genentech and Novartis, and has received research funding from GlaxoSmithKline, Genentech, AstraZeneca, Merck and Myriad.

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Kwong, L., Davies, M. Targeted therapy for melanoma: rational combinatorial approaches. Oncogene 33, 1–9 (2014). https://doi.org/10.1038/onc.2013.34

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