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Melanoma and Other Skin Cancers

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Biotargets of Cancer in Current Clinical Practice

Abstract

Skin cancers are the most prevalent of all malignancies with 50% of all Americans reaching the age of 65 expected to develop one form of skin cancer in their lifetimes. The two most common forms of skin cancer, basal cell carcinoma and squamous cell carcinoma (the so-called nonmelanoma skin cancers), develop from keratinocytes, have a low tendency to metastasize and are less deadly. In contrast, melanomas develop from melanocytes follow an aggressive clinical course and account for the majority of skin cancer deaths. The recent years have seen a giant leap in our understanding of the molecular events that underlie the development and progression of both melanoma and nonmelanoma skin cancers. This has in turn led to the development of targeted therapeutic agents that specifically inhibit the oncogenic mutations that drive these cancers. In this review, we outline the latest knowledge on the etiology, biomarkers, and prognostic classification of both melanoma and nonmelanoma skin cancers. We discuss in detail how the comprehensive genetic analysis of melanoma has led to a number of distinct molecular subgroups of melanoma being described and review the latest literature on the preclinical and clinical development of personalized therapy strategies for both melanoma and nonmelanoma skin cancers. We finally look to the future and describe how the in-depth mutational profiling of patients’ tumors will yield important diagnostic and prognostic information and help guide the choice of therapy.

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References

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.

    Article  PubMed  Google Scholar 

  2. Lachiewicz AM, Berwick M, Wiggins CL, Thomas NE. Epidemiologic support for melanoma heterogeneity using the surveillance, epidemiology, and end results program. J Invest Dermatol. 2008;128(5): 1340–2.

    Article  PubMed  CAS  Google Scholar 

  3. Rigel DS. Epidemiology of melanoma. Semin Cutan Med Surg. 2010;29(4):204–9.

    Article  PubMed  CAS  Google Scholar 

  4. Fisher DE, James WD. Indoor tanning-science, behavior, and policy. N Engl J Med. 2010;363(10): 901–3.

    Article  PubMed  CAS  Google Scholar 

  5. Moan J, Dahlback A, Setlow RB. Epidemiological support for an hypothesis for melanoma induction indicating a role for UVA radiation. Photochem Photobiol. 1999;70(2):243–7.

    Article  PubMed  CAS  Google Scholar 

  6. Holman CD, Armstrong BK. Cutaneous malignant melanoma and indicators of total accumulated exposure to the sun: an analysis separating histogenetic types. J Natl Cancer Inst. 1984;73(1):75–82.

    PubMed  CAS  Google Scholar 

  7. Pfahlberg A, Kolmel KF, Gefeller O. Timing of excessive ultraviolet radiation and melanoma: epidemiology does not support the existence of a critical period of high susceptibility to solar ultraviolet radiation-induced melanoma. Br J Dermatol. 2001; 144(3):471–5.

    Article  PubMed  CAS  Google Scholar 

  8. Pleasance ED, Cheetham RK, Stephens PJ, et al. A comprehensive catalogue of somatic mutations from a human cancer genome. Nature. 2010;463(7278): 191–6.

    Article  PubMed  CAS  Google Scholar 

  9. Green AC, Williams GM, Logan V, Strutton GM. Reduced melanoma after regular sunscreen use: randomized trial follow-up. J Clin Oncol. 2011;29(3): 257–63.

    Article  PubMed  CAS  Google Scholar 

  10. Meyle KD, Guldberg P. Genetic risk factors for melanoma. Hum Genet. 2009;126(4):499–510.

    Article  PubMed  CAS  Google Scholar 

  11. Begg CB, Orlow I, Hummer AJ, et al. Lifetime risk of melanoma in CDKN2A mutation carriers in a population-based sample. J Natl Cancer Inst. 2005; 97(20):1507–15.

    Article  PubMed  CAS  Google Scholar 

  12. Arumi-Uria M, McNutt NS, Finnerty B. Grading of atypia in nevi: correlation with melanoma risk. Mod Pathol. 2003;16(8):764–71.

    Article  PubMed  Google Scholar 

  13. MacKie RM, English J, Aitchison TC, Fitzsimons CP, Wilson P. The number and distribution of benign pigmented moles (melanocytic naevi) in a healthy British population. Br J Dermatol. 1985;113(2): 167–74.

    Article  PubMed  CAS  Google Scholar 

  14. Newton-Bishop JA, Chang YM, Iles MM, et al. Melanocytic nevi, nevus genes, and melanoma risk in a large case-control study in the United Kingdom. Cancer Epidemiol Biomarkers Prev. 2010;19(8): 2043–54.

    Article  PubMed  CAS  Google Scholar 

  15. Balch CM, Soong SJ, Gershenwald JE, et al. Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol. 2001;19(16):3622–34.

    PubMed  CAS  Google Scholar 

  16. Breslow A. Thickness, cross-sectional areas and depth of invasion in the prognosis of cutaneous melanoma. Ann Surg. 1970;172(5):902–8.

    Article  PubMed  CAS  Google Scholar 

  17. Clark Jr WH, From L, Bernardino EA, Mihm MC. The histogenesis and biologic behavior of primary human malignant melanomas of the skin. Cancer Res. 1969;29(3):705–27.

    PubMed  Google Scholar 

  18. Balch CM, Gershenwald JE, Soong SJ, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009;27(36):6199–206.

    Article  PubMed  Google Scholar 

  19. Lens MB, Dawes M, Newton-Bishop JA, Goodacre T. Tumour thickness as a predictor of occult lymph node metastases in patients with stage I and II melanoma undergoing sentinel lymph node biopsy. Br J Surg. 2002;89(10):1223–7.

    Article  PubMed  CAS  Google Scholar 

  20. Sondak VK, Taylor JM, Sabel MS, et al. Mitotic rate and younger age are predictors of sentinel lymph node positivity: lessons learned from the generation of a probabilistic model. Ann Surg Oncol. 2004; 11(3):247–58.

    Article  PubMed  Google Scholar 

  21. Gonzalez U. Cloud over sentinel node biopsy: unlikely survival benefit in melanoma. Arch Dermatol. 2007;143(6):775–6.

    Article  PubMed  Google Scholar 

  22. Kanzler MH. The current status of evaluation and treatment of high-risk cutaneous melanoma: therapeutic breakthroughs remain elusive. Arch Dermatol. 2007;143(6):785–7.

    Article  PubMed  Google Scholar 

  23. Morton DL, Thompson JF, Cochran AJ, et al. Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med. 2006;355(13):1307–17.

    Article  PubMed  CAS  Google Scholar 

  24. Ohsie SJ, Sarantopoulos GP, Cochran AJ, Binder SW. Immunohistochemical characteristics of melanoma. J Cutan Pathol. 2008;35(5):433–44.

    Article  PubMed  Google Scholar 

  25. Prieto VG, Shea CR. Use of immunohistochemistry in melanocytic lesions. J Cutan Pathol. 2008;35 Suppl 2:1–10.

    Article  PubMed  Google Scholar 

  26. Thies A, Berlin A, Brunner G, et al. Glycoconjugate profiling of primary melanoma and its sentinel node and distant metastases: implications for diagnosis and pathophysiology of metastases. Cancer Lett. 2007;248(1):68–80.

    Article  PubMed  CAS  Google Scholar 

  27. Kashani-Sabet M, Rangel J, Torabian S, et al. A multi-marker assay to distinguish malignant melanomas from benign nevi. Proc Natl Acad Sci U S A. 2009;106(15):6268–72.

    Article  PubMed  CAS  Google Scholar 

  28. Carlson JA, Ross JS, Slominski A, et al. Molecular diagnostics in melanoma. J Am Acad Dermatol. 2005;52(5):743–75. quiz 775-748.

    Article  PubMed  Google Scholar 

  29. Gould Rothberg BE, Bracken MB, Rimm DL. Tissue biomarkers for prognosis in cutaneous melanoma: a systematic review and meta-analysis. J Natl Cancer Inst. 2009;101(7):452–74.

    Article  PubMed  CAS  Google Scholar 

  30. Larson AR, Konat E, Alani RM. Melanoma biomarkers: current status and vision for the future. Nat Clin Pract Oncol. 2009;6(2):105–17.

    Article  PubMed  CAS  Google Scholar 

  31. Bosserhoff AK. Novel biomarkers in malignant melanoma. Clin Chim Acta. 2006;367(1–2):28–35.

    Article  PubMed  CAS  Google Scholar 

  32. Gimotty PA, Van Belle P, Elder DE, et al. Biologic and prognostic significance of dermal Ki67 expression, mitoses, and tumorigenicity in thin invasive cutaneous melanoma. J Clin Oncol. 2005;23(31): 8048–56.

    Article  PubMed  Google Scholar 

  33. Haass NK, Smalley KS, Li L, Herlyn M. Adhesion, migration and communication in melanocytes and melanoma. Pigment Cell Res. 2005;18(3):150–9.

    Article  PubMed  CAS  Google Scholar 

  34. Shih IM, Speicher D, Hsu MY, Levine E, Herlyn M. Melanoma cell–cell interactions are mediated through heterophilic Mel-CAM/ligand adhesion. Cancer Res. 1997;57(17):3835–40.

    PubMed  CAS  Google Scholar 

  35. Johnson JP, Bar-Eli M, Jansen B, Markhof E. Melanoma progression-associated glycoprotein MUC18/MCAM mediates homotypic cell adhesion through interaction with a heterophilic ligand. Int J Cancer. 1997;73(5):769–74.

    Article  PubMed  CAS  Google Scholar 

  36. Shih LM, Hsu MY, Palazzo JP, Herlyn M. The cell–cell adhesion receptor Mel-CAM acts as a tumor suppressor in breast carcinoma. Am J Pathol. 1997;151(3):745–51.

    PubMed  CAS  Google Scholar 

  37. Shih IM, Elder DE, Speicher D, Johnson JP, Herlyn M. Isolation and functional characterization of the A32 melanoma-associated antigen. Cancer Res. 1994;54(9):2514–20.

    PubMed  CAS  Google Scholar 

  38. Kraus A, Masat L, Johnson JP. Analysis of the expression of intercellular adhesion molecule-1 and MUC18 on benign and malignant melanocytic lesions using monoclonal antibodies directed against distinct epitopes and recognizing denatured, non-glycosylated antigen. Melanoma Res. 1997;7 Suppl 2:S75–81.

    PubMed  CAS  Google Scholar 

  39. Xie S, Luca M, Huang S, et al. Expression of MCAM/MUC18 by human melanoma cells leads to increased tumor growth and metastasis. Cancer Res. 1997;57(11):2295–303.

    PubMed  CAS  Google Scholar 

  40. Johnson JP, Rummel MM, Rothbacher U, Sers C. MUC18: a cell adhesion molecule with a potential role in tumor growth and tumor cell dissemination. Curr Top Microbiol Immunol. 1996;213(Pt 1): 95–105.

    Article  PubMed  CAS  Google Scholar 

  41. Lehmann JM, Holzmann B, Breitbart EW, Schmiegelow P, Riethmuller G, Johnson JP. Discrimination between benign and malignant cells of melanocytic lineage by two novel antigens, a glycoprotein with a molecular weight of 113,000 and a protein with a molecular weight of 76,000. Cancer Res. 1987;47(3):841–5.

    PubMed  CAS  Google Scholar 

  42. Lehmann JM, Riethmuller G, Johnson JP. MUC18, a marker of tumor progression in human melanoma, shows sequence similarity to the neural cell adhesion molecules of the immunoglobulin superfamily. Proc Natl Acad Sci U S A. 1989;86(24):9891–5.

    Article  PubMed  CAS  Google Scholar 

  43. Pearl RA, Pacifico MD, Richman PI, Wilson GD, Grover R. Stratification of patients by melanoma cell adhesion molecule (MCAM) expression on the basis of risk: implications for sentinel lymph node biopsy. J Plast Reconstr Aesthet Surg. 2008;61(3):265–71.

    Article  PubMed  CAS  Google Scholar 

  44. Pacifico MD, Grover R, Richman PI, Daley FM, Buffa F, Wilson GD. Development of a tissue array for primary melanoma with long-term follow-up: discovering melanoma cell adhesion molecule as an important prognostic marker. Plast Reconstr Surg. 2005;115(2):367–75.

    Article  PubMed  CAS  Google Scholar 

  45. Ostmeier H, Fuchs B, Otto F, et al. Prognostic immunohistochemical markers of primary human melanomas. Br J Dermatol. 2001;145(2):203–9.

    Article  PubMed  CAS  Google Scholar 

  46. Nolte C, Moos M, Schachner M. Immunolocalization of the neural cell adhesion molecule L1 in epithelia of rodents. Cell Tissue Res. 1999;298(2):261–73.

    Article  PubMed  CAS  Google Scholar 

  47. Thies A, Schachner M, Moll I, et al. Overexpression of the cell adhesion molecule L1 is associated with metastasis in cutaneous malignant melanoma. Eur J Cancer. 2002;38(13):1708–16.

    Article  PubMed  CAS  Google Scholar 

  48. Hortsch M. The L1 family of neural cell adhesion molecules: old proteins performing new tricks. Neuron. 1996;17(4):587–93.

    Article  PubMed  CAS  Google Scholar 

  49. Montgomery AM, Becker JC, Siu CH, et al. Human neural cell adhesion molecule L1 and rat homologue NILE are ligands for integrin alpha v beta 3. J Cell Biol. 1996;132(3):475–85.

    Article  PubMed  CAS  Google Scholar 

  50. Voura EB, Ramjeesingh RA, Montgomery AM, Siu CH. Involvement of integrin alpha(v)beta(3) and cell adhesion molecule L1 in transendothelial migration of melanoma cells. Mol Biol Cell. 2001;12(9): 2699–710.

    PubMed  CAS  Google Scholar 

  51. Meier F, Busch S, Gast D, et al. The adhesion molecule L1 (CD171) promotes melanoma progression. Int J Cancer. 2006;119(3):549–55.

    Article  PubMed  CAS  Google Scholar 

  52. Fogel M, Mechtersheimer S, Huszar M, et al. L1 adhesion molecule (CD 171) in development and progression of human malignant melanoma. Cancer Lett. 2003;189(2):237–47.

    Article  PubMed  CAS  Google Scholar 

  53. Talantov D, Mazumder A, Yu JX, et al. Novel genes associated with malignant melanoma but not benign melanocytic lesions. Clin Cancer Res. 2005;11(20): 7234–42.

    Article  PubMed  CAS  Google Scholar 

  54. van de Stolpe A, van der Saag PT. Intercellular adhesion molecule-1. J Mol Med. 1996;74(1):13–33.

    Article  PubMed  Google Scholar 

  55. Johnson JP, Stade BG, Holzmann B, Schwable W, Riethmuller G. De novo expression of intercellular-adhesion molecule 1 in melanoma correlates with increased risk of metastasis. Proc Natl Acad Sci U S A. 1989;86(2):641–4.

    Article  PubMed  CAS  Google Scholar 

  56. Natali P, Nicotra MR, Cavaliere R, et al. Differential expression of intercellular adhesion molecule 1 in primary and metastatic melanoma lesions. Cancer Res. 1990;50(4):1271–8.

    PubMed  CAS  Google Scholar 

  57. Natali PG, Hamby CV, Felding-Habermann B, et al. Clinical significance of alpha(v)beta3 integrin and intercellular adhesion molecule-1 expression in cutaneous malignant melanoma lesions. Cancer Res. 1997;57(8):1554–60.

    PubMed  CAS  Google Scholar 

  58. Schadendorf D, Gawlik C, Haney U, Ostmeier H, Suter L, Czarnetzki BM. Tumour progression and metastatic behaviour in vivo correlates with integrin expression on melanocytic tumours. J Pathol. 1993;170(4):429–34.

    Article  PubMed  CAS  Google Scholar 

  59. Schadendorf D, Heidel J, Gawlik C, Suter L, Czarnetzki BM. Association with clinical outcome of expression of VLA-4 in primary cutaneous malignant melanoma as well as P-selectin and E-selectin on intratumoral vessels. J Natl Cancer Inst. 1995; 87(5):366–71.

    Article  PubMed  CAS  Google Scholar 

  60. Miele ME, Bennett CF, Miller BE, Welch DR. Enhanced metastatic ability of TNF-alpha-treated malignant melanoma cells is reduced by intercellular adhesion molecule-1 (ICAM-1, CD54) antisense oligonucleotides. Exp Cell Res. 1994;214(1):231–41.

    Article  PubMed  CAS  Google Scholar 

  61. Aeed PA, Nakajima M, Welch DR. The role of polymorphonuclear leukocytes (PMN) on the growth and metastatic potential of 13762NF mammary adenocarcinoma cells. Int J Cancer. 1988;42(5):748–59.

    Article  PubMed  CAS  Google Scholar 

  62. Giavazzi R, Chirivi RG, Garofalo A, et al. Soluble intercellular adhesion molecule 1 is released by human melanoma cells and is associated with tumor growth in nude mice. Cancer Res. 1992;52(9):2628–30.

    PubMed  CAS  Google Scholar 

  63. Becker JC, Termeer C, Schmidt RE, Brocker EB. Soluble intercellular adhesion molecule-1 inhibits MHC-restricted specific T cell/tumor interaction. J Immunol. 1993;151(12):7224–32.

    PubMed  CAS  Google Scholar 

  64. Brummer J, Ebrahimnejad A, Flayeh R, et al. cis Interaction of the cell adhesion molecule CEACAM1 with integrin beta(3). Am J Pathol. 2001;159(2): 537–46.

    Article  PubMed  CAS  Google Scholar 

  65. Thies A, Moll I, Berger J, et al. CEACAM1 expression in cutaneous malignant melanoma predicts the development of metastatic disease. J Clin Oncol. 2002;20(10):2530–6.

    Article  PubMed  CAS  Google Scholar 

  66. Ebrahimnejad A, Streichert T, Nollau P, et al. CEACAM1 enhances invasion and migration of melanocytic and melanoma cells. Am J Pathol. 2004;165(5):1781–7.

    Article  PubMed  CAS  Google Scholar 

  67. Hsu MY, Wheelock MJ, Johnson KR, Herlyn M. Shifts in cadherin profiles between human normal melanocytes and melanomas. J Investig Dermatol Symp Proc. 1996;1(2):188–94.

    PubMed  CAS  Google Scholar 

  68. Tang A, Eller MS, Hara M, Yaar M, Hirohashi S, Gilchrest BA. E-cadherin is the major mediator of human melanocyte adhesion to keratinocytes in vitro. J Cell Sci. 1994;107(Pt 4):983–92.

    PubMed  CAS  Google Scholar 

  69. Haass NK, Smalley KS, Herlyn M. The role of altered cell–cell communication in melanoma progression. J Mol Histol. 2004;35(3):309–18.

    Article  PubMed  CAS  Google Scholar 

  70. Haass NK, Herlyn M. Normal human melanocyte homeostasis as a paradigm for understanding melanoma. J Investig Dermatol Symp Proc. 2005;10(2): 153–63.

    Article  PubMed  CAS  Google Scholar 

  71. Danen EH, de Vries TJ, Morandini R, Ghanem GG, Ruiter DJ, van Muijen GN. E-cadherin expression in human melanoma. Melanoma Res. 1996;6(2):127–31.

    Article  PubMed  CAS  Google Scholar 

  72. Sanders DS, Blessing K, Hassan GA, Bruton R, Marsden JR, Jankowski J. Alterations in cadherin and catenin expression during the biological progression of melanocytic tumours. Mol Pathol. 1999;52(3):151–7.

    Article  PubMed  CAS  Google Scholar 

  73. Krengel S, Groteluschen F, Bartsch S, Tronnier M. Cadherin expression pattern in melanocytic tumors more likely depends on the melanocyte environment than on tumor cell progression. J Cutan Pathol. 2004;31(1):1–7.

    Article  PubMed  Google Scholar 

  74. Andersen K, Nesland JM, Holm R, Florenes VA, Fodstad O, Maelandsmo GM. Expression of S100A4 combined with reduced E-cadherin expression predicts patient outcome in malignant melanoma. Mod Pathol. 2004;17(8):990–7.

    Article  PubMed  CAS  Google Scholar 

  75. Nishizawa A, Nakanishi Y, Yoshimura K, et al. Clinicopathologic significance of dysadherin expression in cutaneous malignant melanoma: immunohistochemical analysis of 115 patients. Cancer. 2005;103(8):1693–700.

    Article  PubMed  CAS  Google Scholar 

  76. Atkins MB. The role of cytotoxic chemotherapeutic agents either alone or in combination with biologic response modifiers. In: Kirkwood JK, ed. Molecular Diagnosis, Prevention and Therapy of Melanoma. New York: Marcel Dekker; 2007. p. 1–2

    Google Scholar 

  77. Sawyers C. Targeted cancer therapy. Nature. 2004;432(7015):294–7.

    Article  PubMed  CAS  Google Scholar 

  78. Bauer S, Duensing A, Demetri GD, Fletcher JA. KIT oncogenic signaling mechanisms in imatinib-resistant gastrointestinal stromal tumor: PI3-kinase/AKT is a crucial survival pathway. Oncogene. 2007; 26(54):7560–8.

    Article  PubMed  CAS  Google Scholar 

  79. Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344(14):1031–7.

    Article  PubMed  CAS  Google Scholar 

  80. Curtin JA, Busam K, Pinkel D, Bastian BC. Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol. 2006;24(26):4340–6.

    Article  PubMed  CAS  Google Scholar 

  81. Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med. 2005;353(20):2135–47.

    Article  PubMed  CAS  Google Scholar 

  82. Smalley KS, Nathanson KL, Flaherty KT. Genetic subgrouping of melanoma reveals new opportunities for targeted therapy. Cancer Res. 2009;69(8): 3241–4.

    Article  PubMed  CAS  Google Scholar 

  83. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417 (6892):949–54.

    Article  PubMed  CAS  Google Scholar 

  84. Dhomen N, Marais R. BRAF signaling and targeted therapies in melanoma. Hematol Oncol Clin North Am. 2009;23(3):529–45. ix.

    Article  PubMed  Google Scholar 

  85. Wellbrock C, Karasarides M, Marais R. The RAF proteins take centre stage. Nat Rev Mol Cell Biol. 2004;5(11):875–85.

    Article  PubMed  CAS  Google Scholar 

  86. Garnett MJ, Marais R. Guilty as charged: B-RAF is a human oncogene. Cancer Cell. 2004;6(4):313–9.

    Article  PubMed  CAS  Google Scholar 

  87. Wan PT, Garnett MJ, Roe SM, et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell. 2004;116(6): 855–67.

    Article  PubMed  CAS  Google Scholar 

  88. Smalley KSM. A pivotal role for ERK in the oncogenic behaviour of malignant melanoma? Int J Cancer. 2003;104(5):527–32.

    Article  PubMed  CAS  Google Scholar 

  89. Sherr CJ. G1 phase progression: cycling on cue. Cell. 1994;79(4):551–5.

    Article  PubMed  CAS  Google Scholar 

  90. Bhatt KV, Spofford LS, Aram G, McMullen M, Pumiglia K, Aplin AE. Adhesion control of cyclin D1 and p27Kip1 levels is deregulated in melanoma cells through BRAF-MEK-ERK signaling. Oncogene. 2005;24(21):3459–71.

    Article  PubMed  CAS  Google Scholar 

  91. Wellbrock C, Ogilvie L, Hedley D, et al. V599EB-RAF is an oncogene in melanocytes. Cancer Res. 2004;64(7):2338–42.

    Article  PubMed  CAS  Google Scholar 

  92. Hingorani SR, Jacobetz MA, Robertson GP, Herlyn M, Tuveson DA. Suppression of BRAF(V599E) in human melanoma abrogates transformation. Cancer Res. 2003;63(17):5198–202.

    PubMed  CAS  Google Scholar 

  93. Wellbrock C, Marais R. Elevated expression of MITF counteracts B-RAF-stimulated melanocyte and melanoma cell proliferation. J Cell Biol. 2005;170(5):703–8.

    Article  PubMed  CAS  Google Scholar 

  94. Pollock PM, Harper UL, Hansen KS, et al. High frequency of BRAF mutations in nevi. Nat Genet. 2003;33(1):19–20.

    Article  PubMed  CAS  Google Scholar 

  95. Michaloglou C, Vredeveld LC, Soengas MS, et al. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature. 2005;436(7051):720–4.

    Article  PubMed  CAS  Google Scholar 

  96. Sharpless NE, DePinho RA. Cancer: crime and punishment. Nature. 2005;436(7051):636–7.

    Article  PubMed  CAS  Google Scholar 

  97. Hayward NK. Genetics of melanoma predisposition. Oncogene. 2003;22(20):3053–62.

    Article  PubMed  CAS  Google Scholar 

  98. Tsao H, Goel V, Wu H, Yang G, Haluska FG. Genetic interaction between NRAS and BRAF mutations and PTEN/MMAC1 inactivation in melanoma. J Invest Dermatol. 2004;122(2):337–41.

    Article  PubMed  CAS  Google Scholar 

  99. Stahl JM, Sharma A, Cheung M, et al. Deregulated Akt3 activity promotes development of malignant melanoma. Cancer Res. 2004;64(19):7002–10.

    Article  PubMed  CAS  Google Scholar 

  100. Davies MA, Stemke-Hale K, Tellez C, et al. A novel AKT3 mutation in melanoma tumours and cell lines. Br J Cancer. 2008;99(8):1265–8.

    Article  PubMed  CAS  Google Scholar 

  101. Dankort D, Curley DP, Cartlidge RA, et al. Braf(V600E) cooperates with Pten loss to induce metastatic melanoma. Nat Genet. 2009;41(5):544–52.

    Article  PubMed  CAS  Google Scholar 

  102. Padua RA, Barrass N, Currie GA. A novel transforming gene in a human malignant melanoma cell line. Nature. 1984;311(5987):671–3.

    Article  PubMed  CAS  Google Scholar 

  103. Padua RA, Barrass NC, Currie GA. Activation of N-ras in a human melanoma cell line. Mol Cell Biol. 1985;5(3):582–5.

    PubMed  CAS  Google Scholar 

  104. Downward J. Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer. 2003;3(1):11–22.

    Article  PubMed  CAS  Google Scholar 

  105. Brose MS, Volpe P, Feldman M, et al. BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res. 2002;62(23):6997–7000.

    PubMed  CAS  Google Scholar 

  106. Lin WM, Baker AC, Beroukhim R, et al. Modeling genomic diversity and tumor dependency in malignant melanoma. Cancer Res. 2008;68(3):664–73.

    Article  PubMed  CAS  Google Scholar 

  107. Milagre C, Dhomen N, Geyer FC, et al. A mouse model of melanoma driven by oncogenic KRAS. Cancer Res. 2010;70(13):5549–57.

    Article  PubMed  CAS  Google Scholar 

  108. Whitwam T, Vanbrocklin MW, Russo ME, et al. Differential oncogenic potential of activated RAS isoforms in melanocytes. Oncogene. 2007;26(31): 4563–70.

    Article  PubMed  CAS  Google Scholar 

  109. Dhomen N, Marais R. New insight into BRAF mutations in cancer. Curr Opin Genet Dev. 2007;17(1): 31–9.

    Article  PubMed  CAS  Google Scholar 

  110. Sahai E, Marshall CJ. RHO-GTPases and cancer. Nat Rev Cancer. 2002;2(2):133–42.

    Article  PubMed  Google Scholar 

  111. Mishra PJ, Ha L, Rieker J, et al. Dissection of RAS downstream pathways in melanomagenesis: a role for Ral in transformation. Oncogene. 2010;29(16): 2449–56.

    Article  PubMed  CAS  Google Scholar 

  112. Dumaz N, Hayward R, Martin J, et al. In melanoma, RAS mutations are accompanied by switching signaling from BRAF to CRAF and disrupted cyclic AMP signaling. Cancer Res. 2006;66(19):9483–91.

    Article  PubMed  CAS  Google Scholar 

  113. Woodman SE, Davies MA. Targeting KIT in melanoma: a paradigm of molecular medicine and targeted therapeutics. Biochem Pharmacol. 2010;80(5):568–74.

    Article  PubMed  CAS  Google Scholar 

  114. Rivera RS, Nagatsuka H, Gunduz M, et al. C-kit protein expression correlated with activating mutations in KIT gene in oral mucosal melanoma. Virchows Arch. 2008;452(1):27–32.

    Article  PubMed  CAS  Google Scholar 

  115. Antonescu CR, Busam KJ, Francone TD, et al. L576P KIT mutation in anal melanomas correlates with KIT protein expression and is sensitive to specific kinase inhibition. Int J Cancer. 2007;121(2): 257–64.

    Article  PubMed  CAS  Google Scholar 

  116. Smalley KS, Contractor R, Nguyen TK, et al. Identification of a novel subgroup of melanomas with KIT/cyclin-dependent kinase-4 overexpression. Cancer Res. 2008;68(14):5743–52.

    Article  PubMed  CAS  Google Scholar 

  117. Zandi R, Larsen AB, Andersen P, Stockhausen MT, Poulsen HS. Mechanisms for oncogenic activation of the epidermal growth factor receptor. Cell Signal. 2007;19(10):2013–23.

    Article  PubMed  CAS  Google Scholar 

  118. Scott G, Ewing J, Ryan D, Abboud C. Stem cell factor regulates human melanocyte-matrix interactions. Pigment Cell Res. 1994;7(1):44–51.

    Article  PubMed  CAS  Google Scholar 

  119. Scott G, Liang H, Luthra D. Stem cell factor regulates the melanocyte cytoskeleton. Pigment Cell Res. 1996;9(3):134–41.

    Article  PubMed  CAS  Google Scholar 

  120. Chabot B, Stephenson DA, Chapman VM, Besmer P, Bernstein A. The proto-oncogene c-kit encoding a transmembrane tyrosine kinase receptor maps to the mouse W locus. Nature. 1988;335(6185):88–9.

    Article  PubMed  CAS  Google Scholar 

  121. Witte ON. Steel locus defines new multipotent growth factor. Cell. 1990;63(1):5–6.

    Article  PubMed  CAS  Google Scholar 

  122. Spritz RA, Giebel LB, Holmes SA. Dominant negative and loss of function mutations of the c-kit (mast/stem cell growth factor receptor) proto-oncogene in human piebaldism. Am J Hum Genet. 1992;50(2): 261–9.

    PubMed  CAS  Google Scholar 

  123. Kawa Y, Ito M, Ono H, et al. Stem cell factor and/or endothelin-3 dependent immortal melanoblast and melanocyte populations derived from mouse neural crest cells. Pigment Cell Res. 2000;13 Suppl 8:73–80.

    Article  PubMed  Google Scholar 

  124. Alexeev V, Yoon K. Distinctive role of the cKit receptor tyrosine kinase signaling in mammalian melanocytes. J Invest Dermatol. 2006;126(5): 1102–10.

    Article  PubMed  CAS  Google Scholar 

  125. Hemesath TJ, Price ER, Takemoto C, Badalian T, Fisher DE. MAP kinase links the transcription factor Microphthalmia to c-Kit signalling in melanocytes. Nature. 1998;391(6664):298–301.

    Article  PubMed  CAS  Google Scholar 

  126. Li G, Satyamoorthy K, Herlyn M. N-cadherin-mediated intercellular interactions promote survival and migration of melanoma cells. Cancer Res. 2001;61(9):3819–25.

    PubMed  CAS  Google Scholar 

  127. Monsel G, Ortonne N, Bagot M, Bensussan A, Dumaz N. c-Kit mutants require hypoxia-inducible factor 1alpha to transform melanocytes. Oncogene. 2010;29(2):227–36.

    Article  PubMed  CAS  Google Scholar 

  128. Natali PG, Nicotra MR, Winkler AB, Cavaliere R, Bigotti A, Ullrich A. Progression of human cutaneous melanoma is associated with loss of expression of c-kit proto-oncogene receptor. Int J Cancer. 1992;52(2):197–201.

    Article  PubMed  CAS  Google Scholar 

  129. Lassam N, Bickford S. Loss of c-kit expression in cultured melanoma cells. Oncogene. 1992;7(1):51–6.

    PubMed  CAS  Google Scholar 

  130. Huang S, Luca M, Gutman M, et al. Enforced c-KIT expression renders highly metastatic human melanoma cells susceptible to stem cell factor-induced apoptosis and inhibits their tumorigenic and metastatic potential. Oncogene. 1996;13(11):2339–47.

    PubMed  CAS  Google Scholar 

  131. Huang S, Jean D, Luca M, Tainsky MA, Bar-Eli M. Loss of AP-2 results in downregulation of c-KIT and enhancement of melanoma tumorigenicity and metastasis. EMBO J. 1998;17(15):4358–69.

    Article  PubMed  CAS  Google Scholar 

  132. Smalley KS, Xiao M, Villanueva J, et al. CRAF inhibition induces apoptosis in melanoma cells with non-V600E BRAF mutations. Oncogene. 2009; 28(1):85–94.

    Article  PubMed  CAS  Google Scholar 

  133. Jilaveanu L, Zito C, Lee SJ, et al. Expression of sorafenib targets in melanoma patients treated with carboplatin, paclitaxel and sorafenib. Clin Cancer Res. 2009;15(3):1076–85.

    Article  PubMed  CAS  Google Scholar 

  134. Edwards RH, Ward MR, Wu H, et al. Absence of BRAF mutations in UV-protected mucosal melanomas. J Med Genet. 2004;41(4):270–2.

    Article  PubMed  CAS  Google Scholar 

  135. Bauer J, Buttner P, Murali R, et al. BRAF mutations in cutaneous melanoma are independently associated with age, anatomic site of the primary tumor and the degree of solar elastosis at the primary tumor site. Pigment Cell Melanoma Res. 2011;24(2): 345–51.

    Article  PubMed  CAS  Google Scholar 

  136. Viros A, Fridlyand J, Bauer J, et al. Improving melanoma classification by integrating genetic and morphologic features. PLoS Med. 2008;5(6):e120.

    Article  PubMed  CAS  Google Scholar 

  137. Ellerhorst JA, Greene VR, Ekmekcioglu S, et al. Clinical correlates of NRAS and BRAF mutations in primary human melanoma. Clin Cancer Res. 2011;17(2):229–35.

    Article  PubMed  CAS  Google Scholar 

  138. King AJ, Patrick DR, Batorsky RS, et al. Demonstration of a genetic therapeutic index for tumors expressing oncogenic BRAF by the kinase inhibitor SB-590885. Cancer Res. 2006;66(23): 11100–5.

    Article  PubMed  CAS  Google Scholar 

  139. Tsai J, Lee JT, Wang W, et al. Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proc Natl Acad Sci U S A. 2008;105(8):3041–6.

    Article  PubMed  CAS  Google Scholar 

  140. Haass NK, Sproesser K, Nguyen TK, et al. The mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor AZD6244 (ARRY-142886) induces growth arrest in melanoma cells and tumor regression when combined with docetaxel. Clin Cancer Res. 2008;14(1):230–9.

    Article  PubMed  CAS  Google Scholar 

  141. Solit DB, Garraway LA, Pratilas CA, et al. BRAF mutation predicts sensitivity to MEK inhibition. Nature. 2006;439(7074):358–62.

    Article  PubMed  CAS  Google Scholar 

  142. Wilhelm SM, Carter C, Tang L, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004;64(19):7099–109.

    Article  PubMed  CAS  Google Scholar 

  143. Sharma A, Trivedi NR, Zimmerman MA, Tuveson DA, Smith CD, Robertson GP. Mutant V599EB-Raf regulates growth and vascular development of malignant melanoma tumors. Cancer Res. 2005;65(6):2412–21.

    Article  PubMed  CAS  Google Scholar 

  144. Hauschild A, Agarwala SS, Trefzer U, 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. 2009;27(17):2823–30.

    Article  PubMed  CAS  Google Scholar 

  145. Whittaker S, Kirk R, Hayward R, et al. Gatekeeper mutations mediate resistance to BRAF-targeted therapies. Sci Transl Med. 2010;2(35):35ra41.

    Article  PubMed  CAS  Google Scholar 

  146. Paraiso KH, Fedorenko IV, Cantini LP, et al. Recovery of phospho-ERK activity allows melanoma cells to escape from BRAF inhibitor therapy. Br J Cancer. 2010;102(12):1724–30.

    Article  PubMed  CAS  Google Scholar 

  147. 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(7287):427–30.

    Article  PubMed  CAS  Google Scholar 

  148. Montagut C, Sharma SV, Shioda T, et al. Elevated CRAF as a potential mechanism of acquired resistance to BRAF inhibition in melanoma. Cancer Res. 2008;68(12):4853–61.

    Article  PubMed  CAS  Google Scholar 

  149. Sondergaard JN, Nazarian R, Wang Q, et al. Differential sensitivity of melanoma cell lines with BRAFV600E mutation to the specific Raf inhibitor PLX4032. J Transl Med. 2010;8:39.

    Article  PubMed  CAS  Google Scholar 

  150. Tap WD, Gong KW, Dering J, et al. Pharmacodynamic characterization of the efficacy signals due to selective BRAF inhibition with PLX4032 in malignant melanoma. Neoplasia. 2010;12(8):637–49.

    PubMed  CAS  Google Scholar 

  151. Yang H, Higgins B, Kolinsky K, et al. RG7204 (PLX4032), a selective BRAFV600E inhibitor, displays potent antitumor activity in preclinical melanoma models. Cancer Res. 2010;70(13):5518–27.

    Article  PubMed  CAS  Google Scholar 

  152. Schwartz GK, Robertson S, Shen A, et al. A phase I study of XL281, a selective oral RAF kinase in patients with advanced solid tumors. J Clin Oncol. 2009;27(15s):3513.

    Google Scholar 

  153. Bollag G, Hirth P, Tsai J, et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature. 2009;467:596–9.

    Article  CAS  Google Scholar 

  154. Villanueva J, Cipolla A, Kong J, et al. A kinase switch underlies acquired resistance to BRAF inhibitors. Pigment Cell Melanoma Res. 2009;22(6):136.

    Google Scholar 

  155. Kefford R, Arkenau H, Brown MP, 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. 2010;28(15s):8503.

    Google Scholar 

  156. Smalley KS, Lioni M, Palma MD, et al. Increased cyclin D1 expression can mediate BRAF inhibitor resistance in BRAF V600E-mutated melanomas. Mol Cancer Ther. 2008;7(9):2876–83.

    Article  PubMed  CAS  Google Scholar 

  157. Lazar V, Ecsedi S, Szollosi AG, et al. Characterization of candidate gene copy number alterations in the 11q13 region along with BRAF and NRAS mutations in human melanoma. Mod Pathol. 2009;22(10):1367–78.

    Article  PubMed  CAS  Google Scholar 

  158. Paraiso KH, Xiang Y, Rebecca VW, 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.

    Google Scholar 

  159. Nathanson KL. Using genetics and genomics strategies to personalize therapy for cancer: focus on melanoma. Biochem Pharmacol. 2010;80(5):755–61.

    Article  PubMed  CAS  Google Scholar 

  160. Smalley KS, Contractor R, Haass NK, et al. Ki67 expression levels are a better marker of reduced melanoma growth following MEK inhibitor treatment than phospho-ERK levels. Br J Cancer. 2007;96(3):445–9.

    Article  PubMed  CAS  Google Scholar 

  161. Cartlidge RA, Thomas GR, Cagnol S, et al. Oncogenic BRAF(V600E) inhibits BIM expression to promote melanoma cell survival. Pigment Cell Melanoma Res. 2008;21(5):534–44.

    Article  PubMed  CAS  Google Scholar 

  162. Boisvert-Adamo K, Longmate W, Abel EV, Aplin AE. Mcl-1 is required for melanoma cell resistance to anoikis. Mol Cancer Res. 2009;7(4):549–56.

    Article  PubMed  CAS  Google Scholar 

  163. Boisvert-Adamo K, Aplin AE. Mutant B-RAF mediates resistance to anoikis via Bad and Bim. Oncogene. 2008;27(23):3301–12.

    Article  PubMed  CAS  Google Scholar 

  164. Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363(9):809–19.

    Article  PubMed  CAS  Google Scholar 

  165. Halaban R, Zhang W, Bacchiocchi A, 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 Melanoma Res. 2010;23(2):190–200.

    Article  PubMed  CAS  Google Scholar 

  166. Heidorn SJ, Milagre C, Whittaker S, et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell. 2010; 140(2):209–21.

    Article  PubMed  CAS  Google Scholar 

  167. Rudin CM, Hann CL, Laterra J, et al. Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449. N Engl J Med. 2009;361(12):1173–8.

    Article  PubMed  CAS  Google Scholar 

  168. Yauch RL, Dijkgraaf GJ, Alicke B, et al. Smoothened mutation confers resistance to a hedgehog pathway inhibitor in medulloblastoma. Science. 2009;326: 572–4.

    Article  PubMed  CAS  Google Scholar 

  169. O’Hare T, Shakespeare WC, Zhu X, et al. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell. 2009;16(5):401–12.

    Article  PubMed  CAS  Google Scholar 

  170. Michor F, Hughes TP, Iwasa Y, et al. Dynamics of chronic myeloid leukaemia. Nature. 2005;435(7046): 1267–70.

    Article  PubMed  CAS  Google Scholar 

  171. Nazarian R, Shi H, Wang Q, et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature. 2010;468:973–7.

    Article  PubMed  CAS  Google Scholar 

  172. Emery CM, Vijayendran KG, Zipser MC, et al. MEK1 mutations confer resistance to MEK and B-RAF inhibition. Proc Natl Acad Sci U S A. 2009;106(48):20411–6.

    Article  PubMed  CAS  Google Scholar 

  173. Jiang CC, Lai F, Thorne RF, et al. MEK-Independent survival of B-RAFV600E melanoma cells selected for resistance to apoptosis induced by the RAF inhibitor PLX4720. Clin Cancer Res. 2011;17(4):721–30 doi: 10.1158/1078-0432.

    Google Scholar 

  174. Johannessen CM, Boehm JS, Kim SY, et al. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature. 2010;468:968–72.

    Article  PubMed  CAS  Google Scholar 

  175. Christensen C, Guldberg P. Growth factors rescue cutaneous melanoma cells from apoptosis induced by knockdown of mutated (V 600 E) B-RAF. Oncogene. 2005;24(41):6292–302.

    Article  PubMed  CAS  Google Scholar 

  176. Gray-Schopfer VC, Karasarides M, Hayward R, Marais R. Tumor necrosis factor-alpha blocks apoptosis in melanoma cells when BRAF signaling is inhibited. Cancer Res. 2007;67(1):122–9.

    Article  PubMed  CAS  Google Scholar 

  177. 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(149):ra84.

    Article  PubMed  CAS  Google Scholar 

  178. Konstantinopoulos PA, Karamouzis MV, Papavassiliou AG. Post-translational modifications and regulation of the RAS superfamily of GTPases as anticancer targets. Nat Rev Drug Discov. 2007; 6(7):541–55.

    Article  PubMed  CAS  Google Scholar 

  179. Gajewski TK ND, Johnson J, Linette G, Bucher C, Blaskovich M, Sebti S, Haluska F. Phase II study of the farnesyltransferase inhibitor R115777 in advanced melanoma: CALGB 500104. J Clin Oncol. 2006;24(18S)

    Google Scholar 

  180. Margolin KA, Moon J, Flaherty LE, Lao CD, Akerley WL, Sosman JA, Kirkwood JM, Sondak VK. Randomized phase II trial of sorafenib (SO) with temsirolimus (TEM) or tipifarnib (TIPI) in metastatic melanoma: Southwest Oncology Group Trial S0438. J Clin Oncol. 2010;28:15s.

    Google Scholar 

  181. Hoeflich KP, O’Brien C, Boyd Z, et al. In vivo antitumor activity of MEK and phosphatidylinositol 3-kinase inhibitors in basal-like breast cancer models. Clin Cancer Res. 2009;15(14):4649–64.

    Article  PubMed  CAS  Google Scholar 

  182. Engelman JA, Chen L, Tan X, et al. Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med. 2008;14(12):1351–6.

    Article  PubMed  CAS  Google Scholar 

  183. Jaiswal BS, Janakiraman V, Kljavin NM, 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(5):e5717.

    Article  PubMed  CAS  Google Scholar 

  184. Infante JR, Fecher LA, Nallapareddy S, Gordon MS, Flaherty KT, Cox DS, DeMarini DJ, Morris SR, Burris HA, Messersmith WA. Safety and efficacy results from the first-in-human study of the oral MEK 1/2 inhibitor GSK1120212. J Clin Oncol. 2010;28:7.

    Article  Google Scholar 

  185. Carnahan J, Beltran PJ, Babij C, et al. Selective and potent Raf inhibitors paradoxically stimulate normal cell proliferation and tumor growth. Mol Cancer Ther. 2010;9(8):2399–410.

    Article  PubMed  CAS  Google Scholar 

  186. Kaplan FM, Shao Y, Mayberry MM, Aplin AE. Hyperactivation of MEK-ERK1/2 signaling and resistance to apoptosis induced by the ongenic B-RAF inhibitor, PLX4720, in mutant N-Ras melanoma cell lines. Oncogene. 2010;30:366–71.

    Article  PubMed  CAS  Google Scholar 

  187. Hatzivassiliou G, Song K, Yen I, et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature. 2010;464(7287):431–5.

    Article  PubMed  CAS  Google Scholar 

  188. Heinrich MC, Griffith DJ, Druker BJ, Wait CL, Ott KA, Zigler AJ. Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood. 2000;96(3):925–32.

    PubMed  CAS  Google Scholar 

  189. Terheyden P, Houben R, Pajouh P, Thorns C, Zillikens D, Becker JC. Response to imatinib mesylate depends on the presence of the V559A-mutated KIT oncogene. J Invest Dermatol. 2010;130(1): 314–6.

    Article  PubMed  CAS  Google Scholar 

  190. Jiang X, Zhou J, Yuen NK, et al. Imatinib targeting of KIT-mutant oncoprotein in melanoma. Clin Cancer Res. 2008;14(23):7726–32.

    Article  PubMed  CAS  Google Scholar 

  191. Ashida A, Takata M, Murata H, Kido K, Saida T. Pathological activation of KIT in metastatic tumors of acral and mucosal melanomas. Int J Cancer. 2009;124(4):862–8.

    Article  PubMed  CAS  Google Scholar 

  192. Woodman SE, Trent JC, Stemke-Hale K, et al. Activity of dasatinib against L576P KIT mutant ­melanoma: molecular, cellular, and clinical correlates. Mol Cancer Ther. 2009;8(8):2079–85.

    Article  PubMed  CAS  Google Scholar 

  193. Ugurel S, Hildenbrand R, Zimpfer A, et al. Lack of clinical efficacy of imatinib in metastatic melanoma. Br J Cancer. 2005;92(8):1398–405.

    Article  PubMed  CAS  Google Scholar 

  194. Kim KB, Eton O, Davis DW, et al. Phase II trial of imatinib mesylate in patients with metastatic melanoma. Br J Cancer. 2008;99(5):734–40.

    Article  PubMed  CAS  Google Scholar 

  195. Hodi FS, Friedlander P, Corless CL, et al. Major response to imatinib mesylate in KIT-mutated melanoma. J Clin Oncol. 2008;26(12):2046–51.

    Article  PubMed  CAS  Google Scholar 

  196. Lutzky J, Bauer J, Bastian BC. Dose-dependent, complete response to imatinib of a metastatic mucosal melanoma with a K642E KIT mutation. Pigment Cell Melanoma Res. 2008;21(4):492–3.

    Article  PubMed  Google Scholar 

  197. Satzger I, Kuttler U, Volker B, Schenck F, Kapp A, Gutzmer R. Anal mucosal melanoma with KIT-activating mutation and response to imatinib therapy–case report and review of the literature. Dermatology. 2010;220(1):77–81.

    Article  PubMed  Google Scholar 

  198. Quintas-Cardama A, Lazar AJ, Woodman SE, Kim K, Ross M, Hwu P. Complete response of stage IV anal mucosal melanoma expressing KIT Val560Asp to the multikinase inhibitor sorafenib. Nat Clin Pract Oncol. 2008;5(12):737–40.

    Article  PubMed  CAS  Google Scholar 

  199. Dessinioti C, Antoniou C, Katsambas A, Stratigos AJ. Basal cell carcinoma: what’s new under the sun. Photochem Photobiol. 2010;86(3):481–91.

    Article  PubMed  CAS  Google Scholar 

  200. Goppner D, Leverkus M. Basal cell carcinoma: from the molecular understanding of the pathogenesis to targeted therapy of progressive disease. J Skin Cancer. 2011;2011:650258.

    PubMed  Google Scholar 

  201. Leibovitch I, Huilgol SC, Selva D, Richards S, Paver R. Basal cell carcinoma treated with Mohs surgery in Australia I. Experience over 10 years. J Am Acad Dermatol. 2005;53(3):445–51.

    Article  PubMed  Google Scholar 

  202. Leibovitch I, Huilgol SC, Selva D, Richards S, Paver R. Basal cell carcinoma treated with Mohs surgery in Australia II. Outcome at 5-year follow-up. J Am Acad Dermatol. 2005;53(3):452–7.

    Article  PubMed  Google Scholar 

  203. Hahn H, Wicking C, Zaphiropoulous PG, et al. Mutations of the human homolog of drosophila patched in the nevoid basal cell carcinoma syndrome. Cell. 1996;85(6):841–51.

    Article  PubMed  CAS  Google Scholar 

  204. Johnson RL, Rothman AL, Xie J, et al. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science. 1996;272(5268):1668–71.

    Article  PubMed  CAS  Google Scholar 

  205. Epstein EH. Basal cell carcinomas: attack of the hedgehog. Nat Rev Cancer. 2008;8(10):743–54.

    Article  PubMed  CAS  Google Scholar 

  206. Leibovitch I, Huilgol SC, Selva D, Richards S, Paver R. Basal cell carcinoma treated with Mohs surgery in Australia III. Perineural invasion. J Am Acad Dermatol. 2005;53(3):458–63.

    Article  PubMed  Google Scholar 

  207. Navi D, Huntley A. Imiquimod 5 percent cream and the treatment of cutaneous malignancy. Dermatol Online J. 2004;10(1):4.

    PubMed  Google Scholar 

  208. Stanley MA. Imiquimod and the imidazoquinolones: mechanism of action and therapeutic potential. Clin Exp Dermatol. 2002;27(7):571–7.

    Article  PubMed  CAS  Google Scholar 

  209. Amini S, Viera MH, Valins W, Berman B. Nonsurgical innovations in the treatment of nonmelanoma skin cancer. J Clin Aesthet Dermatol. 2010;3(6):20–34.

    Google Scholar 

  210. Von Hoff DD, LoRusso PM, Rudin CM, et al. Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N Engl J Med. 2009; 361(12):1164–72.

    Article  Google Scholar 

  211. Caro I, Low JA. The role of the hedgehog signaling pathway in the development of basal cell carcinoma and opportunities for treatment. Clin Cancer Res. 2010;16(13):3335–9.

    Article  PubMed  CAS  Google Scholar 

  212. Greinert R. Skin cancer: new markers for better prevention. Pathobiology. 2009;76(2):64–81.

    Article  PubMed  Google Scholar 

  213. Armstrong BK, Kricker A. The epidemiology of UV induced skin cancer. J Photochem Photobiol B. 2001;63(1–3):8–18.

    Article  PubMed  CAS  Google Scholar 

  214. de Gruijl FR, van Kranen HJ, Mullenders LH. UV-induced DNA damage, repair, mutations and oncogenic pathways in skin cancer. J Photochem Photobiol B. 2001;63(1–3):19–27.

    Article  PubMed  Google Scholar 

  215. Lai LW, Ducore JM, Rosenstein BS. DNA-protein crosslinking in normal human skin fibroblasts exposed to solar ultraviolet wavelengths. Photochem Photobiol. 1987;46(1):143–6.

    Article  PubMed  CAS  Google Scholar 

  216. Matsumura Y, Ananthaswamy HN. Molecular mechanisms of photocarcinogenesis. Front Biosci. 2002;7:d765–83.

    Article  PubMed  CAS  Google Scholar 

  217. Karagas MR, Nelson HH, Sehr P, et al. Human papillomavirus infection and incidence of squamous cell and basal cell carcinomas of the skin. J Natl Cancer Inst. 2006;98(6):389–95.

    Article  PubMed  Google Scholar 

  218. Meyer T, Arndt R, Christophers E, Nindl I, Stockfleth E. Importance of human papillomaviruses for the development of skin cancer. Cancer Detect Prev. 2001;25(6):533–47.

    PubMed  CAS  Google Scholar 

  219. Kosmidis M, Dziunycz P, Suarez-Farinas M, et al. Immunosuppression affects CD4+ mRNA expression and induces Th2 dominance in the microenvironment of cutaneous squamous cell carcinoma in organ transplant recipients. J Immunother. 2010; 33(5):538–46.

    Article  PubMed  CAS  Google Scholar 

  220. Cassarino DS, Derienzo DP, Barr RJ. Cutaneous squamous cell carcinoma: a comprehensive clinicopathologic classification–part two. J Cutan Pathol. 2006;33(4):261–79.

    Article  PubMed  Google Scholar 

  221. Cassarino DS, Derienzo DP, Barr RJ. Cutaneous squamous cell carcinoma: a comprehensive clinicopathologic classification. Part one. J Cutan Pathol. 2006;33(3):191–206.

    PubMed  Google Scholar 

  222. Jensen V, Prasad AR, Smith A, et al. Prognostic criteria for squamous cell cancer of the skin. J Surg Res. 2010;159(1):509–16.

    Article  PubMed  CAS  Google Scholar 

  223. Farasat S, Yu SS, Neel VA, et al. A new American Joint Committee on Cancer staging system for cutaneous squamous cell carcinoma: creation and rationale for inclusion of tumor (T) characteristics. J Am Acad Dermatol. 2011;64(6):1051–9.

    Article  PubMed  Google Scholar 

  224. Brown VL, Atkins CL, Ghali L, Cerio R, Harwood CA, Proby CM. Safety and efficacy of 5% imiquimod cream for the treatment of skin dysplasia in high-risk renal transplant recipients: randomized, double-blind, placebo-controlled trial. Arch Dermatol. 2005;141(8):985–93.

    Article  PubMed  CAS  Google Scholar 

  225. Peris K, Micantonio T, Fargnoli MC, Lozzi GP, Chimenti S. Imiquimod 5% cream in the treatment of Bowen’s disease and invasive squamous cell carcinoma. J Am Acad Dermatol. 2006;55(2):324–7.

    Article  PubMed  Google Scholar 

  226. Patel GK, Goodwin R, Chawla M, et al. Imiquimod 5% cream monotherapy for cutaneous squamous cell carcinoma in situ (Bowen’s disease): a randomized, double-blind, placebo-controlled trial. J Am Acad Dermatol. 2006;54(6):1025–32.

    Article  PubMed  Google Scholar 

  227. Nindl I, Gottschling M, Krawtchenko N, et al. Low prevalence of p53, p16(INK4a) and Ha-ras tumour-specific mutations in low-graded actinic keratosis. Br J Dermatol. 2007;156 Suppl 3:34–9.

    Article  PubMed  CAS  Google Scholar 

  228. Ortonne JP. From actinic keratosis to squamous cell carcinoma. Br J Dermatol. 2002;146 Suppl 61:20–3.

    Article  PubMed  Google Scholar 

  229. Muller PA, Vousden KH, Norman JC. p53 and its mutants in tumor cell migration and invasion. J Cell Biol. 2011;192(2):209–18.

    Article  PubMed  CAS  Google Scholar 

  230. Ziegler A, Jonason AS, Leffell DJ, et al. Sunburn and p53 in the onset of skin cancer. Nature. 1994;372(6508):773–6.

    Article  PubMed  CAS  Google Scholar 

  231. Xu Y, Voorhees JJ, Fisher GJ. Epidermal growth factor receptor is a critical mediator of ultraviolet B irradiation-induced signal transduction in immortalized human keratinocyte HaCaT cells. Am J Pathol. 2006;169(3):823–30.

    Article  PubMed  CAS  Google Scholar 

  232. Bachelor MA, Cooper SJ, Sikorski ET, Bowden GT. Inhibition of p38 mitogen-activated protein kinase and phosphatidylinositol 3-kinase decreases UVB-induced activator protein-1 and cyclooxygenase-2 in a SKH-1 hairless mouse model. Mol Cancer Res. 2005;3(2):90–9.

    Article  PubMed  CAS  Google Scholar 

  233. El-Abaseri TB, Fuhrman J, Trempus C, Shendrik I, Tennant RW, Hansen LA. Chemoprevention of UV light-induced skin tumorigenesis by inhibition of the epidermal growth factor receptor. Cancer Res. 2005;65(9):3958–65.

    Article  PubMed  CAS  Google Scholar 

  234. Ke H, Harris R, Coloff JL, et al. The c-Jun NH2-terminal kinase 2 plays a dominant role in human epidermal neoplasia. Cancer Res. 2010;70(8): 3080–8.

    Article  PubMed  CAS  Google Scholar 

  235. Delehedde M, Cho SH, Sarkiss M, et al. Altered expression of bcl-2 family member proteins in nonmelanoma skin cancer. Cancer. 1999;85(7):1514–22.

    Article  PubMed  CAS  Google Scholar 

  236. Pena JC, Rudin CM, Thompson CB. A Bcl-xL transgene promotes malignant conversion of chemically initiated skin papillomas. Cancer Res. 1998;58(10): 2111–6.

    PubMed  CAS  Google Scholar 

  237. Taylor JK, Zhang QQ, Monia BP, Marcusson EG, Dean NM. Inhibition of Bcl-xL expression sensitizes normal human keratinocytes and epithelial cells to apoptotic stimuli. Oncogene. 1999;18(31):4495–504.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

Work in the Smalley lab was supported by The Melanoma Research Foundation, The Bankhead-Coley Research Program (09BN-14), The American Cancer Society (#93-032-13), and the NIH/National Cancer Institute (U54 CA143970-01). The authors thank Drs. Vernon Sondak and Jane Messina for useful discussions and their constructive criticism of the manuscript.

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Correspondence to Keiran S. M. Smalley Ph.D. .

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Paraiso, K.H.T., John, J.K., Smalley, K.S.M. (2012). Melanoma and Other Skin Cancers. In: Bologna, M. (eds) Biotargets of Cancer in Current Clinical Practice. Current Clinical Pathology. Humana Press. https://doi.org/10.1007/978-1-61779-615-9_17

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