Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

From genes to drugs: targeted strategies for melanoma

Nature Reviews Cancer volume 12, pages 349–361 (2012)Cite this article

Subjects

An Author Correction to this article was published on 12 October 2020

This article has been updated

Key Points

  • Oncogenic mutations in melanoma are increasingly well categorized and are not stand-alone events.

  • Several highly recurrent oncogenic mutations in melanoma occur within known signalling pathways. The most common of these is BRAF-V600E, which occurs in approximately 50% of melanomas.

  • Targeted therapies seek to inhibit functionally causative oncoproteins and have shown substantial promise in recent months.

  • Successful targeting of the BRAF-V600E or mutant KIT kinases has produced significant clinical responses in patients with advanced melanoma harbouring those mutations.

  • Targeted inhibition of the immune tolerance checkpoint with a blocking antibody approach has produced significant clinical responses in patients with advanced melanoma.

  • Permanent control of advanced melanoma remains uncommon for suppression of signalling or immune checkpoint targets. Improved strategies focus both on the development of new targeted therapeutics and on the analysis of combinations of these treatments.

Abstract

The past decade has revealed that melanoma is comprised of multiple subclasses that can be categorized on the basis of key features, including the clinical stage of disease, the oncogenic molecular 'drivers', the anatomical location or the behaviour of the primary lesion and the expression of specific biomarkers. Although exercises in subclassification are not new in oncology, progress in this area has produced both conceptual and clinical breakthroughs, which, for melanoma, are unprecedented in the modern history of the disease. This Review focuses on these recent striking advances in the strategy of molecularly targeted approaches to the therapy of melanoma in humans.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Melanocyte differentiation: the MITF axis.
Figure 2: Immunomodulatory signalling.

Similar content being viewed by others

Change history

  • 12 October 2020

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

References

  1. Padua, R. A., Barrass, N. & Currie, G. A. A novel transforming gene in a human malignant melanoma cell line. Nature 311, 671–673 (1984).

    Article  CAS  PubMed  Google Scholar 

  2. van 't Veer, L. J. et al. N.-ras mutations in human cutaneous melanoma from sun-exposed body sites. Mol. Cell. Biol. 9, 3114–3116 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Tsao, H., Goel, V., Wu, H., Yang, G. & Haluska, F. G. Genetic interaction between NRAS and BRAF mutations and PTEN/MMAC1 inactivation in melanoma. J. Invest. Dermatol. 122, 337–341 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Goel, V. K., Lazar, A. J., Warneke, C. L., Redston, M. S. & Haluska, F. G. Examination of mutations in BRAF, NRAS, and PTEN in primary cutaneous melanoma. J. Invest. Dermatol. 126, 154–160 (2006).

    Article  CAS  PubMed  Google Scholar 

  5. Yang, G., Rajadurai, A. & Tsao, H. Recurrent patterns of dual RB and p53 pathway inactivation in melanoma. J. Invest. Dermatol. 125, 1242–1251 (2005).

    Article  CAS  PubMed  Google Scholar 

  6. Daniotti, M. et al. BRAF alterations are associated with complex mutational profiles in malignant melanoma. Oncogene 23, 5968–5977 (2004).

    Article  CAS  PubMed  Google Scholar 

  7. Curtin, J. A. et al. Distinct sets of genetic alterations in melanoma. N. Engl. J. Med. 353, 2135–2147 (2005). This manuscript helped to establish the presence of mutually exclusive, anatomically distinct subsets of melanomas that are driven by different oncogenes.

    Article  CAS  PubMed  Google Scholar 

  8. Smalley, K. S. et al. Increased cyclin D1 expression can mediate BRAF inhibitor resistance in BRAF V600E-mutated melanomas. Mol. Cancer Ther. 7, 2876–2883 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Smalley, K. S. et al. Identification of a novel subgroup of melanomas with KIT/cyclin-dependent kinase-4 overexpression. Cancer Res. 68, 5743–5752 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Topczewska, J. M. et al. Embryonic and tumorigenic pathways converge via Nodal signaling: role in melanoma aggressiveness. Nature Med. 12, 925–932 (2006).

    Article  CAS  PubMed  Google Scholar 

  11. Care, A. et al. HOXB7 constitutively activates basic fibroblast growth factor in melanomas. Mol. Cell. Biol. 16, 4842–4851 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Gupta, P. B. et al. The melanocyte differentiation program predisposes to metastasis after neoplastic transformation. Nature Genet. 37, 1047–1054 (2005).

    Article  CAS  PubMed  Google Scholar 

  13. Weinstein, I. B. & Joe, A. K. Mechanisms of disease: oncogene addiction—a rationale for molecular targeting in cancer therapy. Nature Clin. Pract Oncol. 3, 448–457 (2006).

    Article  CAS  Google Scholar 

  14. Levy, C., Khaled, M. & Fisher, D. E. MITF: master regulator of melanocyte development and melanoma oncogene. Trends Mol. Med. 12, 406–414 (2006).

    Article  CAS  PubMed  Google Scholar 

  15. Garraway, L. A. et al. Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. Nature 436, 117–122 (2005). This study identified genomic amplifications of MITF , a lineage-specific regulator of melanocyte development, as an oncogenic event in a subset of melanomas.

    Article  CAS  PubMed  Google Scholar 

  16. Price, E. R. et al. Lineage-specific signaling in melanocytes. C-kit stimulation recruits p300/CBP to microphthalmia. J. Biol. Chem. 273, 17983–17986 (1998).

    Article  CAS  PubMed  Google Scholar 

  17. Wellbrock, C. et al. Oncogenic BRAF regulates melanoma proliferation through the lineage specific factor MITF. PLoS ONE 3, e2734 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Wu, M. et al. c-Kit triggers dual phosphorylations, which couple activation and degradation of the essential melanocyte factor Mi. Genes Dev. 14, 301–312 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Yokoyama, S. et al. A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma. Nature 480, 99–103 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. McGill, G. G. et al. Bcl2 regulation by the melanocyte master regulator Mitf modulates lineage survival and melanoma cell viability. Cell 109, 707–718 (2002).

    Article  CAS  PubMed  Google Scholar 

  21. Du, J. et al. Critical role of CDK2 for melanoma growth linked to its melanocyte-specific transcriptional regulation by MITF. Cancer Cell 6, 565–576 (2004).

    Article  CAS  PubMed  Google Scholar 

  22. Yokoyama, S. et al. Pharmacologic suppression of MITF expression via HDAC inhibitors in the melanocyte lineage. Pigment Cell Melanoma Res. 21, 457–463 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Yokoyama, S., Salma, N. & Fisher, D. E. MITF pathway mutations in melanoma. Pigment Cell Melanoma Res. 22, 376–377 (2009).

    Article  PubMed  Google Scholar 

  24. Carvajal, R. D. et al. KIT as a therapeutic target in metastatic melanoma. JAMA 305, 2327–2334 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Beadling, C. et al. KIT gene mutations and copy number in melanoma subtypes. Clin. Cancer Res. 14, 6821–6828 (2008).

    Article  CAS  PubMed  Google Scholar 

  26. Webster, J. D., Kiupel, M. & Yuzbasiyan-Gurkan, V. Evaluation of the kinase domain of c-KIT in canine cutaneous mast cell tumors. BMC Cancer 6, 85 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Jiang, X. et al. Imatinib targeting of KIT-mutant oncoprotein in melanoma. Clin. Cancer Res. 14, 7726–7732 (2008).

    Article  CAS  PubMed  Google Scholar 

  28. Hodi, F. S. et al. Major response to imatinib mesylate in KIT-mutated melanoma. J. Clin. Oncol. 26, 2046–2051 (2008).

    Article  CAS  PubMed  Google Scholar 

  29. Lutzky, J., Bauer, J. & Bastian, B. C. Dose-dependent, complete response to imatinib of a metastatic mucosal melanoma with a K642E KIT mutation. Pigment Cell Melanoma Res. 21, 492–493 (2008).

    Article  PubMed  Google Scholar 

  30. Antonescu, C. R. The GIST paradigm: lessons for other kinase-driven cancers. J. Pathol. 223, 251–261 (2011).

    Article  CAS  PubMed  Google Scholar 

  31. Stevens, C. W., Manoharan, T. H. & Fahl, W. E. Characterization of mutagen-activated cellular oncogenes that confer anchorage independence to human fibroblasts and tumorigenicity to NIH 3T3 cells: sequence analysis of an enzymatically amplified mutant HRAS allele. Proc. Natl Acad. Sci. USA 85, 3875–3879 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Yuasa, Y. et al. Mechanism of activation of an N-ras oncogene of SW-1271 human lung carcinoma cells. Proc. Natl Acad. Sci. USA 81, 3670–3674 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Eskandarpour, M. et al. Suppression of oncogenic NRAS by RNA interference induces apoptosis of human melanoma cells. Int. J. Cancer 115, 65–73 (2005).

    Article  CAS  PubMed  Google Scholar 

  34. Yao, K. et al. In vitro hypoxia-conditioned colon cancer cell lines derived from HCT116 and HT29 exhibit altered apoptosis susceptibility and a more angiogenic profile in vivo. Br. J. Cancer 93, 1356–1363 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Sebti, S. M. Protein farnesylation: implications for normal physiology, malignant transformation, and cancer therapy. Cancer Cell 7, 297–300 (2005).

    Article  CAS  PubMed  Google Scholar 

  36. Gajewski, T. K. et al. Phase II study of the farnesyltransferase inhibitor R115777 in advanced melanoma: CALGB 500104. J. Clin. Oncol. Abstr. 24, 8014 (2006).

    Article  Google Scholar 

  37. Dhomen, N. & Marais, R. New insight into BRAF mutations in cancer. Curr. Opin. Genet. Dev. 17, 31–39 (2007).

    Article  CAS  PubMed  Google Scholar 

  38. Alavi, A., Hood, J. D., Frausto, R., Stupack, D. G. & Cheresh, D. A. Role of Raf in vascular protection from distinct apoptotic stimuli. Science 301, 94–96 (2003).

    Article  CAS  PubMed  Google Scholar 

  39. Davies, H. et al. Mutations of the BRAF gene in human cancer. Nature 417, 949–954 (2002). This publication first identified the occurrence of activating mutations in BRAF in melanomas (and in other malignancies).

    Article  CAS  PubMed  Google Scholar 

  40. Smalley, K. S. et al. CRAF inhibition induces apoptosis in melanoma cells with non-V600E BRAF mutations. Oncogene 28, 685–694 (2009).

    Article  CAS  Google Scholar 

  41. Heidorn, S. J. et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell 140, 209–221 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Michaloglou, C. et al. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436, 720–724 (2005).

    Article  CAS  PubMed  Google Scholar 

  43. Wellbrock, C. et al. V599EB-RAF is an oncogene in melanocytes. Cancer Res. 64, 2338–2342 (2004).

    Article  CAS  PubMed  Google Scholar 

  44. Dankort, D. et al. Braf(V600E) cooperates with Pten loss to induce metastatic melanoma. Nature Genet. 41, 544–552 (2009).

    Article  CAS  PubMed  Google Scholar 

  45. Patton, E. E. et al. BRAF mutations are sufficient to promote nevi formation and cooperate with p53 in the genesis of melanoma. Curr. Biol. 15, 249–254 (2005).

    Article  CAS  PubMed  Google Scholar 

  46. Dhomen, N. et al. Oncogenic Braf induces melanocyte senescence and melanoma in mice. Cancer Cell 15, 294–303 (2009).

    Article  CAS  PubMed  Google Scholar 

  47. Hingorani, S. R., Jacobetz, M. A., Robertson, G. P., Herlyn, M. & Tuveson, D. A. Suppression of BRAF(V599E) in human melanoma abrogates transformation. Cancer Res. 63, 5198–5202 (2003).

    CAS  PubMed  Google Scholar 

  48. Karasarides, M. et al. B-RAF is a therapeutic target in melanoma. Oncogene 23, 6292–6298 (2004).

    Article  CAS  PubMed  Google Scholar 

  49. Sumimoto, H. et al. Inhibition of growth and invasive ability of melanoma by inactivation of mutated BRAF with lentivirus-mediated RNA interference. Oncogene 23, 6031–6039 (2004).

    Article  CAS  PubMed  Google Scholar 

  50. Poulikakos, P. I., Zhang, C., Bollag, G., Shokat, K. M. & Rosen, N. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 464, 427–430 (2011).

    Article  CAS  Google Scholar 

  51. Hatzivassiliou, G. et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 464, 431–435 (2010).

    Article  CAS  PubMed  Google Scholar 

  52. Wilhelm, S. 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. 64, 7099–7109 (2004).

    Article  CAS  PubMed  Google Scholar 

  53. Wilhelm, S. et al. Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nature Rev. Drug Discov. 5, 835–844 (2006).

    Article  CAS  Google Scholar 

  54. Ratain, M. et al. Preliminary antitumor activity of BAY 43–9006 in metastatic renal cell carcinoma and other advanced refractory solid tumors in a phase II Randomized Discontinuation Trial (RDT). J.Clin. Oncol. Abstr. 22, 4501 (2004).

    Article  Google Scholar 

  55. Eisen, T. et al. Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis. Br. J. Cancer 95, 581–586 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Flaherty, K. T. et al. Phase I/II, pharmacokinetic and pharmacodynamic trial of BAY 43–9006 alone in patients with metastatic melanoma. J. Clin. Oncol. Abstr. 2005, 3037 (2005).

    Article  Google Scholar 

  57. Schwartz, G. K. et al. A phase I study of XL281, a selective oral RAF kinase inhibitor, in patients (Pts) with advanced solid tumors. J. Clin. Oncol. Abstr. 27, 3513 (2009).

    Article  Google Scholar 

  58. Venetsanakos, E. et al. CHIR-265, a novel inhibitor that targets B-Raf and VEGFR, shows efficacy in a broad range of preclinical models. Proc. Am. Assoc. Cancer Res. Abstr. 47, 4854 (2006).

    Google Scholar 

  59. Sala, E. et al. BRAF silencing by short hairpin RNA or chemical blockade by PLX4032 leads to different responses in melanoma and thyroid carcinoma cells. Mol. Cancer Res. 6, 751–759 (2008).

    Article  CAS  PubMed  Google Scholar 

  60. Kefford, R. et al. Phase I/II study of GSK2118436, a selective inhibitor of oncogenic mutant BRAF kinase, in patients with metastatic melanoma and other solid tumors. J. Clin. Oncol. Abstr. 28, 8503 (2010).

    Article  Google Scholar 

  61. Flaherty, K. T. et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N. Engl. J. Med. 363, 809–819 (2010). This study demonstrated major clinical activity for PLX4032 in its first evaluation in humans.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Chapman, P. B. et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N. Engl. J. Med. 364, 2507–2516 (2011). This clinical study demonstrated enhanced survival features conferred by PLX4032 compared with dacarbazine in patients with advanced melanoma.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Xie, P. et al. The crystal structure of BRAF in complex with an organoruthenium inhibitor reveals a mechanism for inhibition of an active form of BRAF kinase. Biochemistry 48, 5187–5198 (2009).

    Article  CAS  PubMed  Google Scholar 

  64. King, A. J. et al. Demonstration of a genetic therapeutic index for tumors expressing oncogenic BRAF by the kinase inhibitor SB-590885. Cancer Res. 66, 11100–11105 (2006).

    Article  CAS  PubMed  Google Scholar 

  65. Tsai, J. et al. Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proc. Natl Acad. Sci. USA 105, 3041–3046 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Middleton, M. R. et al. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J. Clin. Oncol. 18, 158–166 (2000).

    Article  CAS  PubMed  Google Scholar 

  67. Hauschild, A. et al. Results of a phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma. J. Clin. Oncol. 27, 2823–2830 (2009).

    Article  CAS  PubMed  Google Scholar 

  68. Corominas, M., Kamino, H., Leon, J. & Pellicer, A. Oncogene activation in human benign tumors of the skin (keratoacanthomas): is HRAS involved in differentiation as well as proliferation? Proc. Natl Acad. Sci. USA 86, 6372–6376 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. da Rocha Dias, S. et al. Activated B-RAF is an Hsp90 client protein that is targeted by the anticancer drug 17-allylamino-17-demethoxygeldanamycin. Cancer Res. 65, 10686–10691 (2005).

    Article  CAS  PubMed  Google Scholar 

  70. Solit, D. B. et al. Phase II trial of 17-allylamino-17-demethoxygeldanamycin in patients with metastatic melanoma. Clin. Cancer Res. 14, 8302–8307 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Emery, C. M. et al. MEK1 mutations confer resistance to MEK and B-RAF inhibition. Proc. Natl Acad. Sci. USA 106, 20411–20416 (2009). This paper demonstrates the ability of MEK1 mutations to rescue BRAF-mutant melanomas from small-molecule BRAF inhibitors.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Johannessen, C. M. et al. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 468, 968–972 (2010). This study identified the activation of COT1 as a means of overcoming BRAF-V600E inhibition in melanoma.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Nazarian, R. et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 468, 973–977 (2010). This publication identified the acquisition of resistance to BRAF-targeted therapy via overactivity of the PDGFR signalling pathway or NRAS activation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Paraiso, K. H. et al. PTEN loss confers BRAF inhibitor resistance to melanoma cells through the suppression of BIM expression. Cancer Res. 71, 2750–2760 (2011). This study demonstrates the importance of PTEN loss, altered PI3K pathway activation and BIM expression in modulating the sensitivity to BRAF inhibition of BRAF-V600E-mutated melanomas.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Villanueva, J. 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 18, 683–695 (2010). This study demonstrates the functionally important roles of MEK and the IGF1R pathway in conferring resistance to BRAF-V600E-targeted melanoma therapy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Davies, B. R. et al. AZD6244 (ARRY-142886), a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 kinases: mechanism of action in vivo, pharmacokinetic/pharmacodynamic relationship, and potential for combination in preclinical models. Mol. Cancer Ther. 6, 2209–2219 (2007).

    Article  CAS  PubMed  Google Scholar 

  77. Lorusso, P. et al. A phase 1–2 clinical study of a second generation oral MEK inhibitor, PD 0325901 in patients with advanced cancer. J. Clin. Oncol Abstr. 23, 3011 (2005).

    Article  Google Scholar 

  78. Solit, D. B. et al. BRAF mutation predicts sensitivity to MEK inhibition. Nature 439, 358–362 (2006).

    Article  CAS  PubMed  Google Scholar 

  79. Dummer, R. et al. AZD6244 (ARRY-142886) vs temozolomide (TMZ) in patients (pts) with advanced melanoma: an open-label, randomized, multicenter, phase II study. J. Clin. Oncol. 26, 9033 (2008).

    Article  Google Scholar 

  80. Infante, J. R. et al. Safety and efficacy results from the first-in-human study of the oral MEK 1/2 inhibitor GSK1120212. J. Clin. Oncol. Abstr. 28, 2503 (2010).

    Article  Google Scholar 

  81. Van Raamsdonk, C. D. et al. Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature 457, 599–602 (2009).

    Article  CAS  PubMed  Google Scholar 

  82. Guldberg, P. et al. Disruption of the MMAC1/PTEN gene by deletion or mutation is a frequent event in malignant melanoma. Cancer Res. 57, 3660–3663 (1997).

    CAS  PubMed  Google Scholar 

  83. Wu, H., Goel, V. & Haluska, F. G. PTEN signaling pathways in melanoma. Oncogene 22, 3113–3122 (2003).

    Article  CAS  PubMed  Google Scholar 

  84. Molhoek, K. R., Brautigan, D. L. & Slingluff, C. L. Jr. Synergistic inhibition of human melanoma proliferation by combination treatment with B-Raf inhibitor BAY43–9006 and mTOR inhibitor Rapamycin. J. Transl. Med. 3, 39 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Meier, F. et al. The RAS/RAF/MEK/ERK and PI3K/AKT signaling pathways present molecular targets for the effective treatment of advanced melanoma. Front. Biosci. 10, 2986–3001 (2005).

    Article  CAS  PubMed  Google Scholar 

  86. Stahl, J. M. et al. Deregulated Akt3 activity promotes development of malignant melanoma. Cancer Res. 64, 7002–7010 (2004).

    Article  CAS  PubMed  Google Scholar 

  87. Smalley, K. S. et al. An organometallic protein kinase inhibitor pharmacologically activates p53 and induces apoptosis in human melanoma cells. Cancer Res. 67, 209–217 (2007).

    Article  CAS  PubMed  Google Scholar 

  88. Romano, M. F. et al. Rapamycin inhibits doxorubicin-induced NF-κB/Rel nuclear activity and enhances the apoptosis of melanoma cells. Eur. J. Cancer 40, 2829–2836 (2004).

    Article  CAS  PubMed  Google Scholar 

  89. Margolin, K. et al. CCI-779 in metastatic melanoma: a phase II trial of the California Cancer Consortium. Cancer 104, 1045–1048 (2005).

    Article  CAS  PubMed  Google Scholar 

  90. Thallinger, C. et al. Comparison of a treatment strategy combining CCI-779 plus DTIC versus DTIC monotreatment in human melanoma in SCID mice. J. Invest. Dermatol. 127, 2411–2417 (2007).

    Article  CAS  PubMed  Google Scholar 

  91. Wang, Y. & Becker, D. Differential expression of the cyclin-dependent kinase inhibitors p16 and p21 in the human melanocytic system. Oncogene 12, 1069–1075 (1996).

    CAS  PubMed  Google Scholar 

  92. Jonsson, G. et al. Genomic profiling of malignant melanoma using tiling-resolution arrayCGH. Oncogene 26, 4738–4748 (2007).

    Article  CAS  PubMed  Google Scholar 

  93. Kamb, A. et al. A cell cycle regulator potentially involved in genesis of many tumor types. Science 264, 436–440 (1994).

    Article  CAS  PubMed  Google Scholar 

  94. Rotolo, S. et al. Effects on proliferation and melanogenesis by inhibition of mutant BRAF and expression of wild-type INK4A in melanoma cells. Int. J. Cancer 115, 164–169 (2005).

    Article  CAS  PubMed  Google Scholar 

  95. O'Dwyer P. J. et al. A phase I dose escalation trial of a daily oral CDK 4/6 inhibitor PD-0332991. J. Clin. Oncol. Abstr. 25, 3550 (2007).

    Article  Google Scholar 

  96. Muthusamy, V. et al. Amplification of CDK4 and MDM2 in malignant melanoma. Genes Chromosomes Cancer 45, 447–454 (2006).

    Article  CAS  PubMed  Google Scholar 

  97. Shangary, S. et al. Reactivation of p53 by a specific MDM2 antagonist (MI-43) leads to p21-mediated cell cycle arrest and selective cell death in colon cancer. Mol. Cancer Ther. 7, 1533–1542 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Potti, A. et al. Immunohistochemical determination of vascular endothelial growth factor (VEGF) overexpression in malignant melanoma. Anticancer Res. 23, 4023–4026 (2003).

    CAS  PubMed  Google Scholar 

  99. Reed, J. A., McNutt, N. S., Prieto, V. G. & Albino, A. P. Expression of transforming growth factor-β2 in malignant melanoma correlates with the depth of tumor invasion. Implications for tumor progression. Am. J. Pathol. 145, 97–104 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Straume, O. & Akslen, L. A. Importance of vascular phenotype by basic fibroblast growth factor, and influence of the angiogenic factors basic fibroblast growth factor/fibroblast growth factor receptor-1 and ephrin-A1/EphA2 on melanoma progression. Am. J. Pathol. 160, 1009–1019 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Barnhill, R. L., Xiao, M., Graves, D. & Antoniades, H. N. Expression of platelet-derived growth factor (PDGF)-A, PDGF-B and the PDGF-α receptor, but not the PDGF-β receptor, in human malignant melanoma in vivo. Br. J. Dermatol. 135, 898–904 (1996).

    Article  CAS  PubMed  Google Scholar 

  102. Rofstad, E. K. & Halsor, E. F. Vascular endothelial growth factor, interleukin 8, platelet-derived endothelial cell growth factor, and basic fibroblast growth factor promote angiogenesis and metastasis in human melanoma xenografts. Cancer Res. 60, 4932–4938 (2000).

    CAS  PubMed  Google Scholar 

  103. Forsberg, K., Valyi-Nagy, I., Heldin, C. H., Herlyn, M. & Westermark, B. Platelet-derived growth factor (PDGF) in oncogenesis: development of a vascular connective tissue stroma in xenotransplanted human melanoma producing PDGF-BB. Proc. Natl Acad. Sci. USA 90, 393–397 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Nurnberg, W., Tobias, D., Otto, F., Henz, B. M. & Schadendorf, D. Expression of interleukin-8 detected by in situ hybridization correlates with worse prognosis in primary cutaneous melanoma. J. Pathol. 189, 546–551 (1999).

    Article  CAS  PubMed  Google Scholar 

  105. Ugurel, S., Rappl, G., Tilgen, W. & Reinhold, U. Increased serum concentration of angiogenic factors in malignant melanoma patients correlates with tumor progression and survival. J. Clin. Oncol. 19, 577–583 (2001).

    Article  CAS  PubMed  Google Scholar 

  106. Varker, K. A. et al. A randomized phase 2 trial of bevacizumab with or without daily low-dose interferon alfa-2b in metastatic malignant melanoma. Ann. Surg. Oncol. 14, 2367–2376 (2007).

    Article  PubMed  Google Scholar 

  107. Fruehauf, J. P. et al. Axitinib (AG-013736) in patients with metastatic melanoma: a phase II study. J. Clin. Oncol. Abstr. 26, 9006 (2008).

    Article  Google Scholar 

  108. Clark, W. H. Jr. et al. Model predicting survival in stage I melanoma based on tumor progression. J. Natl Cancer Inst. 81, 1893–1904 (1989).

    Article  PubMed  Google Scholar 

  109. Ferradini, L. et al. Analysis of T cell receptor variability in tumor-infiltrating lymphocytes from a human regressive melanoma. Evidence for in situ T cell clonal expansion. J. Clin. Invest. 91, 1183–1190 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Van den Eynde, B. & Brichard, V. G. New tumor antigens recognized by T cells. Curr. Opin. Immunol. 7, 674–681 (1995).

    Article  CAS  PubMed  Google Scholar 

  111. Van den Eynde, B. et al. Presence on a human melanoma of multiple antigens recognized by autologous CTL. Int. J. Cancer 44, 634–640 (1989).

    Article  CAS  PubMed  Google Scholar 

  112. Van den Eynde, B. et al. A new family of genes coding for an antigen recognized by autologous cytolytic T lymphocytes on a human melanoma. J. Exp. Med. 182, 689–698 (1995).

    Article  CAS  PubMed  Google Scholar 

  113. van der Bruggen, P. et al. A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science 254, 1643–1647 (1991).

    Article  CAS  PubMed  Google Scholar 

  114. Van Der Bruggen, P. et al. Tumor-specific shared antigenic peptides recognized by human T cells. Immunol. Rev. 188, 51–64 (2002).

    Article  CAS  PubMed  Google Scholar 

  115. Brichard, V. et al. The tyrosinase gene codes for an antigen recognized by autologous cytolytic T lymphocytes on HLA-A2 melanomas. J. Exp. Med. 178, 489–495 (1993).

    Article  CAS  PubMed  Google Scholar 

  116. Coulie, P. G. et al. A new gene coding for a differentiation antigen recognized by autologous cytolytic T lymphocytes on HLA-A2 melanomas. J. Exp. Med. 180, 35–42 (1994).

    Article  CAS  PubMed  Google Scholar 

  117. Kabbinavar, F. et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J. Clin. Oncol. 21, 60–65 (2003).

    Article  CAS  PubMed  Google Scholar 

  118. Kawakami, Y. et al. Cloning of the gene coding for a shared human melanoma antigen recognized by autologous T cells infiltrating into tumor. Proc. Natl Acad. Sci. USA 91, 3515–3519 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Kawakami, Y. et al. Identification of a human melanoma antigen recognized by tumor-infiltrating lymphocytes associated with in vivo tumor rejection. Proc. Natl Acad. Sci. USA 91, 6458–6462 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Kawakami, Y. et al. Identification of the immunodominant peptides of the MART-1 human melanoma antigen recognized by the majority of HLA-A2-restricted tumor infiltrating lymphocytes. J. Exp. Med. 180, 347–352 (1994).

    Article  CAS  PubMed  Google Scholar 

  121. Kawakami, Y., Sumimoto, H., Fujita, T. & Matsuzaki, Y. Immunological detection of altered signaling molecules involved in melanoma development. Cancer Metastasis Rev. 24, 357–366 (2005).

    Article  CAS  PubMed  Google Scholar 

  122. Robbins, P. F. et al. A mutated β-catenin gene encodes a melanoma-specific antigen recognized by tumor infiltrating lymphocytes. J. Exp. Med. 183, 1185–1192 (1996).

    Article  CAS  PubMed  Google Scholar 

  123. Wolfel, T. et al. A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma. Science 269, 1281–1284 (1995).

    Article  CAS  PubMed  Google Scholar 

  124. Machiels, J. P., van Baren, N. & Marchand, M. Peptide-based cancer vaccines. Semin. Oncol. 29, 494–502 (2002).

    Article  CAS  PubMed  Google Scholar 

  125. Young, J. W. & Inaba, K. Dendritic cells as adjuvants for class I major histocompatibility complex-restricted antitumor immunity. J. Exp. Med. 183, 7–11 (1996).

    Article  CAS  PubMed  Google Scholar 

  126. Zhang, S., Wang, Q. & Miao, B. Review: dendritic cell-based vaccine in the treatment of patients with advanced melanoma. Cancer Biother. Radiopharm. 22, 501–507 (2007).

    Article  CAS  PubMed  Google Scholar 

  127. Cerundolo, V., Hermans, I. F. & Salio, M. Dendritic cells: a journey from laboratory to clinic. Nature Immunol. 5, 7–10 (2004).

    Article  CAS  Google Scholar 

  128. Banchereau, J. et al. Immune and clinical responses in patients with metastatic melanoma to CD34+ progenitor-derived dendritic cell vaccine. Cancer Res. 61, 6451–6458 (2001).

    CAS  PubMed  Google Scholar 

  129. Su, Z. et al. Immunological and clinical responses in metastatic renal cancer patients vaccinated with tumor RNA-transfected dendritic cells. Cancer Res. 63, 2127–2133 (2003).

    CAS  PubMed  Google Scholar 

  130. Schuler-Thurner, B. et al. Rapid induction of tumor-specific type 1 T helper cells in metastatic melanoma patients by vaccination with mature, cryopreserved, peptide-loaded monocyte-derived dendritic cells. J. Exp. Med. 195, 1279–1288 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Mullins, D. W. et al. Route of immunization with peptide-pulsed dendritic cells controls the distribution of memory and effector T cells in lymphoid tissues and determines the pattern of regional tumor control. J. Exp. Med. 198, 1023–1034 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Dhodapkar, M. V., Steinman, R. M., Krasovsky, J., Munz, C. & Bhardwaj, N. Antigen-specific inhibition of effector T cell function in humans after injection of immature dendritic cells. J. Exp. Med. 193, 233–238 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Fay, J. W. et al. Long-term outcomes in patients with metastatic melanoma vaccinated with melanoma peptide-pulsed CD34+ progenitor-derived dendritic cells. Cancer Immunol. Immunother. 55, 1209–1218 (2006).

    Article  CAS  PubMed  Google Scholar 

  134. Slingluff, C. L. Jr. et al. Clinical and immunologic results of a randomized phase II trial of vaccination using four melanoma peptides either administered in granulocyte-macrophage colony-stimulating factor in adjuvant or pulsed on dendritic cells. J. Clin. Oncol. 21, 4016–4026 (2003).

    Article  CAS  PubMed  Google Scholar 

  135. Fong, L. et al. Altered peptide ligand vaccination with Flt3 ligand expanded dendritic cells for tumor immunotherapy. Proc. Natl Acad. Sci. USA 98, 8809–8814 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Krieg, A. M. CpG motifs: the active ingredient in bacterial extracts? Nature Med. 9, 831–835 (2003).

    Article  CAS  PubMed  Google Scholar 

  137. Srivastava, P. K. Peptide-binding heat shock proteins in the endoplasmic reticulum: role in immune response to cancer and in antigen presentation. Adv. Cancer Res. 62, 153–177 (1993).

    Article  CAS  PubMed  Google Scholar 

  138. Smyth, M. J. et al. NKT cells - conductors of tumor immunity? Curr. Opin. Immunol. 14, 165–171 (2002).

    Article  CAS  PubMed  Google Scholar 

  139. Rosenberg, S. A. et al. Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma. Nature Med. 4, 321–327 (1998).

    Article  CAS  PubMed  Google Scholar 

  140. Coulie, P. G. et al. Cytolytic T-cell responses of cancer patients vaccinated with a MAGE antigen. Immunol. Rev. 188, 33–42 (2002).

    Article  CAS  PubMed  Google Scholar 

  141. Bendandi, M. et al. Complete molecular remissions induced by patient-specific vaccination plus granulocyte-monocyte colony-stimulating factor against lymphoma. Nature Med. 5, 1171–1177 (1999).

    Article  CAS  PubMed  Google Scholar 

  142. Hodi, F. S. & Dranoff, G. Genetically modified tumor cell vaccines. Surg. Oncol. Clin. N. Am. 7, 471–485 (1998).

    Article  CAS  PubMed  Google Scholar 

  143. Dranoff, G. et al. Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc. Natl Acad. Sci. USA 90, 3539–3543 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Mach, N. et al. Differences in dendritic cells stimulated in vivo by tumors engineered to secrete granulocyte-macrophage colony-stimulating factor or Flt3-ligand. Cancer Res. 60, 3239–3246 (2000).

    CAS  PubMed  Google Scholar 

  145. Huang, A. Y. et al. Role of bone marrow-derived cells in presenting MHC class I-restricted tumor antigens. Science 264, 961–965 (1994).

    Article  CAS  PubMed  Google Scholar 

  146. Shen, Z., Reznikoff, G., Dranoff, G. & Rock, K. L. Cloned dendritic cells can present exogenous antigens on both MHC class I and class II molecules. J. Immunol. 158, 2723–2730 (1997).

    CAS  PubMed  Google Scholar 

  147. Hung., K. et al. The central role of CD4+ T cells in the antitumor immune response. J. Exp. Med. 188, 2357–2368 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Soiffer, R. et al. Vaccination with irradiated autologous melanoma cells engineered to secrete human granulocyte-macrophage colony-stimulating factor generates potent antitumor immunity in patients with metastatic melanoma. Proc. Natl Acad. Sci. USA 95, 13141–13146 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Soiffer, R. et al. Vaccination with irradiated, autologous melanoma cells engineered to secrete granulocyte-macrophage colony-stimulating factor by adenoviral-mediated gene transfer augments antitumor immunity in patients with metastatic melanoma. J. Clin. Oncol. 21, 3343–3350 (2003).

    Article  CAS  PubMed  Google Scholar 

  150. Chambers, C. A., Sullivan, T. J. & Allison, J. P. Lymphoproliferation in CTLA-4-deficient mice is mediated by costimulation-dependent activation of CD4+ T cells. Immunity 7, 885–895 (1997).

    Article  CAS  PubMed  Google Scholar 

  151. Leach, D. R., Krummel, M. F. & Allison, J. P. Enhancement of antitumor immunity by CTLA-4 blockade. Science 271, 1734–1736 (1996).

    Article  CAS  PubMed  Google Scholar 

  152. van Elsas, A. et al. Elucidating the autoimmune and antitumor effector mechanisms of a treatment based on cytotoxic T lymphocyte antigen-4 blockade in combination with a B16 melanoma vaccine: comparison of prophylaxis and therapy. J. Exp. Med. 194, 481–489 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Phan, G. Q. et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc. Natl Acad. Sci. USA 100, 8372–8377 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. O'Day, S. J. et al. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. Ann. Oncol. 21, 1712–1717 (2010).

    Article  CAS  PubMed  Google Scholar 

  155. Wolchok, J. D. et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 11, 155–164 (2010).

    Article  CAS  PubMed  Google Scholar 

  156. Wolchok, J. D. & Saenger, Y. The mechanism of anti-CTLA-4 activity and the negative regulation of T-cell activation. Oncologist 13, 2–9 (2008).

    Article  CAS  PubMed  Google Scholar 

  157. Lens, M., Ferrucci, P. F. & Testori, A. Anti-CTLA4 monoclonal antibody Ipilimumab in the treatment of metastatic melanoma: recent findings. Recent Pat. Anticancer Drug Discov. 3, 105–113 (2008).

    Article  CAS  PubMed  Google Scholar 

  158. Fong, L. & Small, E. J. Anti-cytotoxic T-lymphocyte antigen-4 antibody: the first in an emerging class of immunomodulatory antibodies for cancer treatment. J. Clin. Oncol. 26, 5275–5283 (2008).

    Article  CAS  PubMed  Google Scholar 

  159. O'Day, S. J., Hamid, O. & Urba, W. J. Targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4): a novel strategy for the treatment of melanoma and other malignancies. Cancer 110, 2614–2627 (2007).

    Article  CAS  PubMed  Google Scholar 

  160. Keilholz, U. CTLA-4: negative regulator of the immune response and a target for cancer therapy. J. Immunother. 31, 431–439 (2008).

    Article  CAS  PubMed  Google Scholar 

  161. Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010). This study reports a Phase III trial demonstrating a survival advantage with the use of anti-CTLA4 (immune checkpoint blockade) in patients with metastatic melanoma.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Robert, C. et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N. Engl. J. Med. 364, 2517–2526 (2011). This report demonstrates improved efficacy for combination therapy using anti-CTLA4 (ipilimumab) plus dacarbazine in patients with metastatic melanoma.

    Article  CAS  PubMed  Google Scholar 

  163. Iwai, Y. et al. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc. Natl Acad. Sci. USA 99, 12293–12297 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Cai, G. et al. PD-1 ligands, negative regulators for activation of naive, memory, and recently activated human CD4+ T cells. Cell. Immunol. 230, 89–98 (2004).

    Article  CAS  PubMed  Google Scholar 

  165. Freeman, G. J. et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J. Exp. Med. 192, 1027–1034 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Watts, T. H. TNF/TNFR family members in costimulation of T cell responses. Annu. Rev. Immunol. 23, 23–68 (2005).

    Article  CAS  PubMed  Google Scholar 

  167. Herman, A. E., Freeman, G. J., Mathis, D. & Benoist, C. CD4+CD25+ T regulatory cells dependent on ICOS promote regulation of effector cells in the prediabetic lesion. J. Exp. Med. 199, 1479–1489 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Shimizu, J., Yamazaki, S. & Sakaguchi, S. Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. J. Immunol. 163, 5211–5218 (1999).

    CAS  PubMed  Google Scholar 

  169. Kusmartsev, S. & Gabrilovich, D. I. Inhibition of myeloid cell differentiation in cancer: the role of reactive oxygen species. J. Leukoc. Biol. 74, 186–196 (2003).

    Article  CAS  PubMed  Google Scholar 

  170. Chang, D. H. et al. Sustained expansion of NKT cells and antigen-specific T cells after injection of α-galactosyl-ceramide loaded mature dendritic cells in cancer patients. J. Exp. Med. 201, 1503–1517 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Kwon, B., Lee, H. W. & Kwon, B. S. New insights into the role of 4–1BB in immune responses: beyond CD8+ T cells. Trends Immunol. 23, 378–380 (2002).

    Article  CAS  PubMed  Google Scholar 

  172. Kwon, B. S. et al. Immune responses in 4–1BB (CD137)-deficient mice. J. Immunol. 168, 5483–5490 (2002).

    Article  CAS  PubMed  Google Scholar 

  173. Schultze, J. L., Grabbe, S. & von Bergwelt-Baildon, M. S. DCs and CD40-activated B cells: current and future avenues to cellular cancer immunotherapy. Trends Immunol. 25, 659–664 (2004).

    Article  CAS  PubMed  Google Scholar 

  174. Vonderheide, R. et al. Clinical activity and immune modulation in cancer patients treated with CP-870,893, a novel CD40 agonist monoclonal antibody. J. Clin. Oncol. 25, 876–883 (2007).

    Article  CAS  PubMed  Google Scholar 

  175. Vonderheide, R. H. & June, C. H. A translational bridge to cancer immunotherapy: exploiting costimulation and target antigens for active and passive T cell immunotherapy. Immunol. Res. 27, 341–56 (2003).

    Article  CAS  PubMed  Google Scholar 

  176. Dannull, J. et al. Enhancing the immunostimulatory function of dendritic cells by transfection with mRNA encoding OX40 ligand. Blood 105, 3206–3213 (2005).

    Article  CAS  PubMed  Google Scholar 

  177. Curtin, J. A., Busam, K., Pinkel, D. & Bastian, B. C. Somatic activation of KIT in distinct subtypes of melanoma. J. Clin. Oncol. 24, 4340–4346 (2006).

    Article  CAS  PubMed  Google Scholar 

  178. Prickett, T. D. et al. Analysis of the tyrosine kinome in melanoma reveals recurrent mutations in ERBB4. Nature Genet. 41, 1127–1132 (2009).

    Article  CAS  PubMed  Google Scholar 

  179. Bastian, B. C., LeBoit, P. E., Hamm, H., Brocker, E. B. & Pinkel, D. Chromosomal gains and losses in primary cutaneous melanomas detected by comparative genomic hybridization. Cancer Res. 58, 2170–2175 (1998).

    CAS  PubMed  Google Scholar 

  180. Moore, S. R. et al. Detection of copy number alterations in metastatic melanoma by a DNA fluorescence in situ hybridization probe panel and array comparative genomic hybridization: a southwest oncology group study (S9431). Clin. Cancer Res. 14, 2927–2935 (2008).

    Article  CAS  PubMed  Google Scholar 

  181. Kraehn, G. M. et al. Extra c-myc oncogene copies in high risk cutaneous malignant melanoma and melanoma metastases. Br. J. Cancer 84, 72–79 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Jane-Valbuena, J. et al. An oncogenic role for ETV1 in melanoma. Cancer Res. 70, 2075–2084 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Freedberg, D. E. et al. Frequent p16-independent inactivation of p14ARF in human melanoma. J. Natl Cancer Inst. 100, 784–95 (2008).

    Article  CAS  PubMed  Google Scholar 

  184. Soussi, T., Kato, S., Levy, P. P. & Ishioka, C. Reassessment of the TP53 mutation database in human disease by data mining with a library of TP53 missense mutations. Hum. Mutat. 25, 6–17 (2005).

    Article  CAS  PubMed  Google Scholar 

  185. Harbour, J. W. et al. Frequent mutation of BAP1 in metastasizing uveal melanomas. Science 330, 1410–1413 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Stark, M. & Hayward, N. Genome-wide loss of heterozygosity and copy number analysis in melanoma using high-density single-nucleotide polymorphism arrays. Cancer Res. 67, 2632–2642 (2007).

    Article  CAS  PubMed  Google Scholar 

  187. Guo, J. 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, 2904–2909 (2011).

    Article  CAS  PubMed  Google Scholar 

  188. Flaherty, K. T. et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N. Engl. J. Med. 363, 809–819 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Hauschild, A. et al. Multicenter phase II trial of the histone deacetylase inhibitor pyridylmethyl-N-{4-[(2-aminophenyl)-carbamoyl]-benzyl}-carbamate in pretreated metastatic melanoma. Melanoma Res. 18, 274–278 (2008).

    Article  CAS  PubMed  Google Scholar 

  190. Bertolotto et al. A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma. Nature 480, 94–98 (2011).

    Article  CAS  PubMed  Google Scholar 

  191. Su, F. et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N. Eng. J. Med 366, 207–215 (2012).

    Article  CAS  Google Scholar 

  192. Poulikos, I. et al. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature 480, 387–390 (2011).

    Article  CAS  Google Scholar 

  193. Shi, H. et al. Melanoma whole-exome sequencing identifies V600EB-RAF amplification-mediated acquired B-RAF inhibitor resistance. Nature Comm. 3, 724 (2012).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors apologize to the numerous colleagues whose important contributions could not be included in this Review owing to space limitations.

Author information

Authors and Affiliations

  1. Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, 02114, Massachusetts, USA

    Keith T. Flaherty & David E. Fisher

  2. Dana Farber Cancer Institute, Boston, 02115, Massachusetts, USA

    F. Stephen Hodi

Authors
  1. Keith T. Flaherty
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. F. Stephen Hodi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David E. Fisher
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David E. Fisher.

Ethics declarations

Competing interests

K.T.F. serves as a consultant to GlaxoSmithKline and Roche/Genentech. F.S.H. has served as a consultant to Amgen and as a non-paid consultant for Bristol-Myers Squibb, Genentech and Novartis. He receives clinical research support from Bristol-Myers Squibb, Genentech, Novartis, Synta Pharmaceuticals and Pfizer. D.E.F. declares no competing financial interests.

Related links

Glossary

Driver mutations

Sequence alterations in a cancer cell that influence the corresponding proteins to result in stimulation of cancerous activity within a cell.

Melanocyte

Melanin pigment-producing cell, usually located within the epidermis; the neoplastic transformation of this cell type gives rise to a nevus (benign) or melanoma (malignant).

Targeted therapy

A treatment designed to block a specific molecular species that is known to be functionally important.

Lineage-restricted oncogenes

Oncogenes the expression of which is limited to certain cell types.

Oncogene addiction

Tumour cell dependency on the molecular activity of an oncogene.

Mucosal

Referring to the cellular lining along internal cavities such as the gastrointestinal, genitourinary, oral or respiratory tracts.

Acral

Refers to hairless skin regions, such as palms and soles.

Solar elastosis

Sun-induced chronic damage to elastin and other connective tissue components within the dermis, typically seen in older people following chronic sun exposure.

Nevus

Benign pigmented lesion with features of senescence that can exhibit varying degrees of growth irregularity that may be concerning for transformation to melanoma. Melanocytic nevus refers to a benign pigmented lesion composed of nests of melanocytes.

G protein-coupled receptor

(GPCR). Family of cell surface transmembrane proteins that are regulated by extracellular ligands to modulate intracellular signalling via interactions with cofactors, the interaction of which is mediated by guanine nucleotide molecules.

Uveal melanoma

Melanoma arising in one of three anatomic locations within the eye: the iris, the choroid or the ciliary body.

Cell cycle checkpoints

Nodal points in the cell cycle that regulate the ability of the cyclin-dependent kinases to induce the progression through the phases of the cell cycle.

Humoral immune responses

Immune responses mediated by antibodies.

Pheresis

Removal of a blood component, as in removal of autologous dendritic cells (antigen-presenting cells), which may be used for adoptive transfer.

Hazard ratio

The effect of a variable on the hazard (or risk) of an event occurring.

Autologous

Pertaining to the host.

Freund's adjuvant

A water-oil emulsion (to which Mycobacterium Tuberculosis is sometimes added, complete Freund's adjuvant), which may potentiate immune responses when incorporated into a vaccine.

Immune checkpoint

Nodal point within signalling pathways that modulates the ability of the immune system to mount a robust response against a specific antigen or group of antigens.

Myeloid suppressor cells

Cells of the myeloid (granulocytic) lineage that inhibit immune responsiveness and may limit antitumour immunity.

Adoptive transfer

A therapeutic strategy consisting of the removal of cells (typically immune cells), ex vivo modulation (such as population expansion) and the re-infusion of cells.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Flaherty, K., Hodi, F. & Fisher, D. From genes to drugs: targeted strategies for melanoma. Nat Rev Cancer 12, 349–361 (2012). https://doi.org/10.1038/nrc3218

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc3218

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer