Therapeutic Kinase Inhibitors pp 99-117

Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 355)

Beyond BRAF in Melanoma

Chapter

Abstract

Recent progress in the analysis of genetic alterations in melanoma has identified recurrent mutations that result in the activation of critical signaling pathways promoting growth and survival of tumors cells. Alterations in the RAS-RAF-MAP kinase and PI3-kinase signaling pathways are commonly altered in melanoma. Mutations in BRAF, NRAS, KIT, and GNAQ occur in a mutually exclusive pattern and lead to MAP-kinase activation. Loss of PTEN function, primarily by deletion, is the most common known genetic alteration in the PI3-kinase cascade, and is commonly associated with BRAF mutations (Curtin et al., N Engl J Med 353:2135–2147, 2005; Tsao et al., Cancer Res 60:1800–1804, 2000, J Investig Dermatol 122:337–341, 2004). The growth advantage conveyed by the constitutive activation of these pathways leads to positive selection of cells that have acquired the mutations and in many instances leads to critical dependency of the cancer cells on their activation. This creates opportunities for therapeutic interventions targeted at signaling components within these pathways that are amenable for pharmacological inhibition. This concept follows the paradigm established by the landmark discovery that inhibition of the fusion kinase BCR-ABL can be used to treat chronic myelogenous leukemia (Druker et al., N Engl J Med 344:1031–037, 2001). The review will focus primarily on kinases involved in signaling that are currently being evaluated for therapeutic intervention in melanoma.

References

  1. Adjei AA, Cohen RB, Franklin W et al (2008) Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers. J Clin Oncol 26:2139–2146. doi:10.1200/JCO.2007.14.4956 PubMedCrossRefGoogle Scholar
  2. Ahmed NU, Ueda M, Ito A et al (1997) Expression of fibroblast growth factor receptors in naevus-cell naevus and malignant melanoma. Melanoma Res 7:299–305PubMedCrossRefGoogle Scholar
  3. Ashman LK (1999) The biology of stem cell factor and its receptor C-kit. Int J Biochem Cell Biol 31:1037–1051. doi:10.1016/S1357-2725(99)00076-X PubMedCrossRefGoogle Scholar
  4. Bastian BC, Kashani-Sabet M, Hamm H et al (2000a) Gene amplifications characterize acral melanoma and permit the detection of occult tumor cells in the surrounding skin. Cancer Res 60:1968–1973PubMedGoogle Scholar
  5. Bastian BC, LeBoit PE, Pinkel D (2000b) Mutations and copy number increase of HRAS in Spitz nevi with distinctive histopathological features. Amn J Pathol 157:967–972CrossRefGoogle Scholar
  6. Bastian BC, Olshen AB, LeBoit PE, Pinkel D (2003) Classifying melanocytic tumors based on DNA copy number changes. Am J Pathol 163:1765–1770PubMedCrossRefGoogle Scholar
  7. Bauer J, Curtin JA, Pinkel D, Bastian BC (2007) Congenital melanocytic nevi frequently harbor NRAS mutations but no BRAF mutations. J Invest Dermatol 127:179–182PubMedCrossRefGoogle Scholar
  8. Beadling C, Jacobson-Dunlop E, Hodi FS et al (2008) KIT gene mutations and copy number in melanoma subtypes. Clin Cancer Res 14:6821–6828. doi:14/21/6821 PubMedCrossRefGoogle Scholar
  9. Besmer P, Murphy JE, George PC et al (1986) A new acute transforming feline retrovirus and relationship of its oncogene v-kit with the protein kinase gene family. Nature 320:415–421. doi:10.1038/320415a0 PubMedCrossRefGoogle Scholar
  10. Birck A, Ahrenkiel V, Zeuthen J et al (2000) Mutation and allelic loss of the PTEN/MMAC1 gene in primary and metastatic melanoma biopsies. J Invest Dermatol 114:277–280PubMedCrossRefGoogle Scholar
  11. Brannan CI, Lyman SD, Williams DE et al (1991) Steel-Dickie mutation encodes a c-kit ligand lacking transmembrane and cytoplasmic domains. Proc Natl Acad Sci U S A 88:4671–4674PubMedCrossRefGoogle Scholar
  12. Buac K, Xu M, Cronin J et al (2009) NRG1/ERBB3 signaling in melanocyte development and melanoma: inhibition of differentiation and promotion of proliferation. Pigment Cell Melanoma Res 22:773–784. doi:10.1111/j.1755-148X.2009.00616.x PubMedCrossRefGoogle Scholar
  13. Carvajal R, Chapman P, Wolchok J et al (2009) A phase II study of imatinib mesylate (IM) for patients with advanced melanoma harboring somatic alterations of KIT. J Clin Oncol (Meeting Abstracts) (15S):9001Google Scholar
  14. Chudnovsky Y, Adams AE, Robbins PB et al (2005) Use of human tissue to assess the oncogenic activity of melanoma-associated mutations. Nat Genet 37:745–749. doi:ng1586 PubMedCrossRefGoogle Scholar
  15. Cronin JC, Wunderlich J, Loftus SK et al (2009) Frequent mutations in the MITF pathway in melanoma. Pigment Cell Melanoma Res 22:435–444. doi:10.1111/j.1755-148X.2009.00578.x PubMedCrossRefGoogle Scholar
  16. Curtin JA, Fridlyand J, Kageshita T et al (2005) Distinct sets of genetic alterations in melanoma. N Engl J Med 353:2135–2147PubMedCrossRefGoogle Scholar
  17. Curtin JA, Busam K, Pinkel D, Bastian BC (2006) Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol 24:4340–4346PubMedCrossRefGoogle Scholar
  18. Dai DL, Martinka M, Li G (2005) Prognostic significance of activated Akt expression in melanoma: a clinicopathologic study of 292 cases. J Clin Oncol 23:1473–1482. doi:10.1200/JCO.2005.07.168 PubMedCrossRefGoogle Scholar
  19. Davies H, Bignell GR, Cox C et al (2002) Mutations of the BRAF gene in human cancer. Nature 417:949–954. doi:10.1038/nature00766 PubMedCrossRefGoogle Scholar
  20. Davies MA, Stemke-Hale K, Tellez C et al (2008) A novel AKT3 mutation in melanoma tumours and cell lines. Br J Cancer 99:1265–1268. doi:10.1038/sj.bjc.6604637 PubMedCrossRefGoogle Scholar
  21. Delord J, Houede N, Awada A et al (2010) First-in-human phase I safety, pharmacokinetic (PK), and pharmacodynamic (PD) analysis of the oral MEK-inhibitor AS703026 [two regimens (R)] in patients (pts) with advanced solid tumors. J Clin Oncol 28Google Scholar
  22. Dhawan P, Singh AB, Ellis DL, Richmond A (2002) Constitutive activation of Akt/protein kinase B in melanoma leads to up-regulation of nuclear factor-kappaB and tumor progression. Cancer Res 62:7335–7342PubMedGoogle Scholar
  23. Djerf EA, Trinks C, Abdiu A et al (2009) ErbB receptor tyrosine kinases contribute to proliferation of malignant melanoma cells: inhibition by gefitinib (ZD1839). Melanoma Res 19:156–166. doi:10.1097/CMR.0b013e32832c6339 PubMedCrossRefGoogle Scholar
  24. Druker BJ, Talpaz M, Resta DJ et al (2001) Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 344:1031–1037. doi:10.1056/NEJM200104053441401 PubMedCrossRefGoogle Scholar
  25. Dummer R, Robert C, Chapman PB et al (2008) AZD6244 (ARRY-142886) vs temozolomide (TMZ) in patients (pts) with advanced melanoma: An open-label, randomized, multicenter, phase II study. J Clin Oncol 26Google Scholar
  26. Economou MA, All-Ericsson C, Bykov V et al (2008) Receptors for the liver synthesized growth factors IGF-1 and HGF/SF in uveal melanoma: intercorrelation and prognostic implications. Acta Ophthalmol 86(Thesis 4):20–25. doi:10.1111/j.1755-3768.2008.01182.x PubMedGoogle Scholar
  27. Eder JP, Appleman L, Heath E et al (2011) A phase I study of a novel spectrum selective kinase inhibitor (SSKI), XL880, administered orally in patients (pts) with advanced solid tumors (STs).–ASCO. http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=40&abstractID=32125. Accessed 3 Jun 2011
  28. Ehlers JP, Harbour JW (2006) Molecular pathobiology of uveal melanoma. Int Ophthalmol Clin 46:167–180PubMedCrossRefGoogle Scholar
  29. Fry DW, Bedford DC, Harvey PH et al (2001) Cell cycle and biochemical effects of PD 0183812. A potent inhibitor of the cyclin D-dependent kinases CDK4 and CDK6. J Biol Chem 276:16617–16623. doi:10.1074/jbc.M008867200 PubMedCrossRefGoogle Scholar
  30. Gartside MG, Chen H, Ibrahimi OA et al (2009) Loss-of-function fibroblast growth factor receptor-2 mutations in melanoma. Mol Cancer Res 7:41–54. doi:10.1158/1541-7786.MCR-08-0021 PubMedCrossRefGoogle Scholar
  31. Giehl KA, Nägele U, Volkenandt M, Berking C (2007) Protein expression of melanocyte growth factors (bFGF, SCF) and their receptors (FGFR-1, c-kit) in nevi and melanoma. J Cutan Pathol 34:7–14. doi:10.1111/j.1600-0560.2006.00569.x PubMedCrossRefGoogle Scholar
  32. Gogas HJ, Kirkwood JM, Sondak VK (2007) Chemotherapy for metastatic melanoma: time for a change? Cancer 109:455–464. doi:10.1002/cncr.22427 PubMedCrossRefGoogle Scholar
  33. Guertin DA, Sabatini DM (2005) An expanding role for mTOR in cancer. Trends Mol Med 11:353–361. doi:10.1016/j.molmed.2005.06.007 PubMedCrossRefGoogle Scholar
  34. Guldberg P, Straten PT, Birck A et al (1997) Disruption of the mmac1/pten gene by deletion or mutation is a frequent event in malignant melanoma. Cancer Res 57:3660–3663PubMedGoogle Scholar
  35. Halaban R, Langdon R, Birchall N et al (1988a) Basic fibroblast growth factor from human keratinocytes is a natural mitogen for melanocytes. J Cell Biol 107:1611–1619PubMedCrossRefGoogle Scholar
  36. Halaban R, Kwon BS, Ghosh S et al (1988b) bFGF as an autocrine growth factor for human melanomas. Oncogene Res 3:177–186PubMedGoogle Scholar
  37. Hodi FS, Friedlander P, Corless CL et al (2008) Major response to imatinib mesylate in KIT-mutated melanoma. J Clin Oncol 26:2046–2051PubMedCrossRefGoogle Scholar
  38. Hsu M-Y, Meier F, Herlyn M (2002) Melanoma development and progression: a conspiracy between tumor and host. Differentiation 70:522–536. doi:10.1046/j.1432-0436.2002.700906.x PubMedCrossRefGoogle Scholar
  39. Infante JR, Fecher LA, Nallapareddy S et al (2010) Safety and efficacy results from the first-in-human study of the oral MEK 1/2 inhibitor GSK1120212. J Clin Oncol 28Google Scholar
  40. Inman JL, Kute T, White W et al (2003) Absence of HER2 overexpression in metastatic malignant melanoma. J Surg Oncol 84:82–88. doi:10.1002/jso.10297 PubMedCrossRefGoogle Scholar
  41. Jemal A, Siegel R, Ward E et al (2009) Cancer statistics, 2009. CA Cancer J Clin 59:225–249. doi:10.3322/caac.20006 PubMedCrossRefGoogle Scholar
  42. Khan MA, Andrews S, Ismail-Khan R et al (2006) Overall and progression-free survival in metastatic melanoma: analysis of a single-institution database. Cancer Control 13:211–217PubMedGoogle Scholar
  43. Kim KB, Eton O, Davis DW et al (2008) Phase II trial of imatinib mesylate in patients with metastatic melanoma. Br J Cancer 99:734–740. doi:10.1038/sj.bjc.6604482 PubMedCrossRefGoogle Scholar
  44. Kluger HM, DiVito K, Berger AJ et al (2004) Her2/neu is not a commonly expressed therapeutic target in melanoma–a large cohort tissue microarray study. Melanoma Res 14:207–210PubMedCrossRefGoogle Scholar
  45. Kunisada T, Yoshida H, Yamazaki H et al (1998) Transgene expression of steel factor in the basal layer of epidermis promotes survival, proliferation, differentiation and migration of melanocyte precursors. Development 125:2915–2923PubMedGoogle Scholar
  46. Kunisada T, Yamazaki H, Hirobe T et al (2000) Keratinocyte expression of transgenic hepatocyte growth factor affects melanocyte development, leading to dermal melanocytosis. Mech Dev 94:67–78PubMedCrossRefGoogle Scholar
  47. Lassam N, Bickford S (1992) Loss of C-Kit expression in cultured melanoma-cells. Oncogene 7:51–56PubMedGoogle Scholar
  48. Linos E, Swetter SM, Cockburn MG et al (2009) Increasing burden of melanoma in the United States. J Invest Dermatol 129:1666–1674. doi:10.1038/jid.2008.423 PubMedCrossRefGoogle Scholar
  49. Longley BJ Jr, Morganroth GS, Tyrrell L et al (1993) Altered metabolism of mast-cell growth factor (c-kit ligand) in cutaneous mastocytosis. N Engl J Med 328:1302–1307. doi:10.1056/NEJM199305063281803 PubMedCrossRefGoogle Scholar
  50. Lutzky J, Bauer J, Bastian BC (2008) Dose-dependent, complete response to imatinib of a metastatic mucosal melanoma with a K642E KIT mutation. Pigment Cell Melanoma Res 21(4):492–495PubMedCrossRefGoogle Scholar
  51. Ma XM, Blenis J (2009) Molecular mechanisms of mTOR-mediated translational control. Nat Rev Mol Cell Biol 10:307–318. doi:10.1038/nrm2672 PubMedCrossRefGoogle Scholar
  52. Maira S-M, Stauffer F, Brueggen J et al (2008) Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol Cancer Ther 7:1851–1863. doi:10.1158/1535-7163.MCT-08-0017 PubMedCrossRefGoogle Scholar
  53. Maldonado JL, Fridlyand J, Patel H et al (2003) Determinants of BRAF mutations in primary melanoma. J Natl Cancer Inst 95:1878–1890PubMedCrossRefGoogle Scholar
  54. Margolin K, Longmate J, Baratta T et al (2005) CCI-779 in metastatic melanoma: a phase II trial of the California Cancer consortium. Cancer 104:1045–1048. doi:10.1002/cncr.21265 PubMedCrossRefGoogle Scholar
  55. Matsui Y, Zsebo KM, Hogan BL (1990) Embryonic expression of a haematopoietic growth factor encoded by the Sl locus and the ligand for c-kit. Nature 347:667–669. doi:10.1038/347667a0 PubMedCrossRefGoogle Scholar
  56. McGovern VJ, Cochran AJ, Van der Esch EP et al (1986) The classification of malignant melanoma, its histological reporting and registration: a revision of the 1972 Sydney classification. Pathology 18:12–21PubMedCrossRefGoogle Scholar
  57. Mita MM, Mita AC, Chu QS et al (2008) Phase I trial of the novel mammalian target of rapamycin inhibitor deforolimus (AP23573; MK-8669) administered intravenously daily for 5 days every 2 weeks to patients with advanced malignancies. J Clin Oncol 26:361–367. doi:10.1200/JCO.2007.12.0345 PubMedCrossRefGoogle Scholar
  58. Montone KT, Belle P, Elder DE (1997) Proto-oncogene c-kit expression in malignant melanoma: protein loss with tumor progression. Mod Pathol 10(9):939–944PubMedGoogle Scholar
  59. Natali PG, Nicotra MR, Winkler AB et al (1992) Progression of human cutaneous melanoma is associated with loss of expression of C-Kit protooncogene receptor. Int J Cancer 52:197–201PubMedCrossRefGoogle Scholar
  60. Nesbit M, Nesbit HK, Bennett J et al (1999) Basic fibroblast growth factor induces a transformed phenotype in normal human melanocytes. Oncogene 18:6469–6476. doi:10.1038/sj.onc.1203066 PubMedCrossRefGoogle Scholar
  61. Noonan FP, Otsuka T, Bang S et al (2000) Accelerated ultraviolet radiation-induced carcinogenesis in hepatocyte growth factor/scatter factor transgenic mice. Cancer Res 60:3738–3743PubMedGoogle Scholar
  62. O’Dwyer PJ, LoRusso P, DeMichele A et al (2007) A phase I dose escalation trial of a daily oral CDK 4/6 inhibitor PD-0332991. J Clin Oncol 2007 ASCO Ann Meet Proc 25Google Scholar
  63. Padua RA, Barrass NC, Currie GA (1985) Activation of N-ras in a human melanoma cell line. Mol Cell Biol 5:582–585PubMedGoogle Scholar
  64. Palavalli LH, Prickett TD, Wunderlich JR et al (2009) Analysis of the matrix metalloproteinase family reveals that MMP8 is often mutated in melanoma. Nat Genet 41:518–520. doi:10.1038/ng.340 PubMedCrossRefGoogle Scholar
  65. Patel S, Bedikian A, Kim K et al (2011) A phase II study of gefitinib in patients with metastatic melanoma.–ASCO. http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=65&abstractID=34308. Accessed 3 Jun 2011
  66. Potti A, Moazzam N, Langness E et al (2004) Immunohistochemical determination of HER-2/neu, c-Kit (CD117), and vascular endothelial growth factor (VEGF) overexpression in malignant melanoma. J Cancer Res Clin Oncol 130:80–86PubMedCrossRefGoogle Scholar
  67. Prickett TD, Agrawal NS, Wei X et al (2009) Analysis of the tyrosine kinome in melanoma reveals recurrent mutations in ERBB4. Nat Genet 41:1127–1132. doi:10.1038/ng.438 PubMedCrossRefGoogle Scholar
  68. Puri N, Ahmed S, Janamanchi V et al (2007) c-Met is a potentially new therapeutic target for treatment of human melanoma. Clin Cancer Res 13:2246–2253. doi:10.1158/1078-0432.CCR-06-0776 PubMedCrossRefGoogle Scholar
  69. Rákosy Z, Vízkeleti L, Ecsedi S et al (2007) EGFR gene copy number alterations in primary cutaneous malignant melanomas are associated with poor prognosis. Int J Cancer 121:1729–1737. doi:10.1002/ijc.22928 PubMedCrossRefGoogle Scholar
  70. Reifenberger J, Wolter M, Bostrom J et al (2000) Allelic losses on chromosome arm 10q and mutation of the PTEN (MMAC1) tumour suppressor gene in primary and metastatic malignant melanomas. Virchows Arch 436:487–493PubMedCrossRefGoogle Scholar
  71. Sarker D, Molife R, Evans TRJ et al (2008) A phase I pharmacokinetic and pharmacodynamic study of TKI258, an oral, multitargeted receptor tyrosine kinase inhibitor in patients with advanced solid tumors. Clin Cancer Res 14:2075–2081. doi:10.1158/1078-0432.CCR-07-1466 PubMedCrossRefGoogle Scholar
  72. Sauter ER, Nesbit M, Tichansky D et al (2001) Fibroblast growth factor-binding protein expression changes with disease progression in clinical and experimental human squamous epithelium. Int J Cancer 92:374–381PubMedCrossRefGoogle Scholar
  73. Sauter ER, Yeo UC, Von Stemm A et al (2002) Cyclin D1 is a candidate oncogene in cutaneous melanoma. Cancer Res 62:3200–3206PubMedGoogle Scholar
  74. Serrano M, Lee H, Chin L et al (1996) Role of the INK4a locus in tumor suppression and cell mortality. Cell 85:27–37PubMedCrossRefGoogle Scholar
  75. Shapiro GI (2006) Cyclin-dependent kinase pathways as targets for cancer treatment. J Clin Oncol 24:1770–1783. doi:10.1200/JCO.2005.03.7689 PubMedCrossRefGoogle Scholar
  76. Sherr CJ, Roberts JM (1999) CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 13:1501–1512PubMedCrossRefGoogle Scholar
  77. Smalley KSM, Lioni M, Dalla Palma M et al (2008) Increased cyclin D1 expression can mediate BRAF inhibitor resistance in BRAF V600E-mutated melanomas. Mol Cancer Ther 7:2876–2883. doi:10.1158/1535-7163.MCT-08-0431 PubMedCrossRefGoogle Scholar
  78. Soni R, O’Reilly T, Furet P et al (2001) Selective in vivo and in vitro effects of a small molecule inhibitor of cyclin-dependent kinase 4. J Natl Cancer Inst 93:436–446PubMedCrossRefGoogle Scholar
  79. Sousa SF, Fernandes PA, Ramos MJ (2008) Farnesyltransferase inhibitors: a detailed chemical view on an elusive biological problem. Curr Med Chem 15:1478–1492PubMedCrossRefGoogle Scholar
  80. Sparrow LE, Heenan PJ (1999) Differential expression of epidermal growth factor receptor in melanocytic tumours demonstrated by immunohistochemistry and mRNA in situ hybridization. Australas J Dermatol 40:19–24PubMedCrossRefGoogle Scholar
  81. Stahl JM, Sharma A, Cheung M et al (2004) Deregulated Akt3 activity promotes development of malignant melanoma. Cancer Res 64:7002–7010PubMedCrossRefGoogle Scholar
  82. Straume O, Akslen LA (2002) 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. doi:10.1016/S0002-9440(10)64922-X PubMedCrossRefGoogle Scholar
  83. Takayama H, LaRochelle WJ, Sharp R et al (1997) Diverse tumorigenesis associated with aberrant development in mice overexpressing hepatocyte growth factor/scatter factor. Proc Natl Acad Sci U S A 94:701–706PubMedCrossRefGoogle Scholar
  84. Tran MA, Gowda R, Sharma A et al (2008) Targeting V600EB-Raf and Akt3 using nanoliposomal-small interfering RNA inhibits cutaneous melanocytic lesion development. Cancer Res 68:7638–7649. doi:10.1158/0008-5472.CAN-07-6614 PubMedCrossRefGoogle Scholar
  85. Trent JM, Meyskens FL, Salmon SE et al (1990) Relation of cytogenetic abnormalities and clinical outcome in metastatic melanoma. N Engl J Med 322:1508–1511PubMedCrossRefGoogle Scholar
  86. Tsao H, Zhang X, Fowlkes K, Haluska FG (2000) Relative reciprocity of NRAS and PTEN/MMAC1 alterations in cutaneous melanoma cell lines. Cancer Res 60:1800–1804PubMedGoogle Scholar
  87. Tsao H, Goel V, Wu H et al (2004) Genetic interaction between NRAS and BRAF mutations and PTEN/MMAC1 inactivation in melanoma. J Investig Dermatol 122:337–341PubMedCrossRefGoogle Scholar
  88. Ueda M, Funasaka Y, Ichihashi M, Mishima Y (1994) Stable and strong expression of basic fibroblast growth factor in naevus cell naevus contrasts with aberrant expression in melanoma. Br J Dermatol 130:320–324PubMedCrossRefGoogle Scholar
  89. Ueno Y, Sakurai H, Tsunoda S et al (2008) Heregulin-induced activation of ErbB3 by EGFR tyrosine kinase activity promotes tumor growth and metastasis in melanoma cells. Int J Cancer 123:340–347. doi:10.1002/ijc.23465 PubMedCrossRefGoogle Scholar
  90. Ugurel S, Hildenbrand R, Zimpfer A et al (2005) Lack of clinical efficacy of imatinib in metastatic melanoma. Br J Cancer 92:1398–1405PubMedCrossRefGoogle Scholar
  91. van Dijk M, Sprenger S, Rombout P et al (2003) Distinct chromosomal aberrations in sinonasal mucosal melanoma as detected by comparative genomic hybridization. Genes Chromosom Cancer 36:151–158PubMedCrossRefGoogle Scholar
  92. Van Raamsdonk CD, Bezrookove V, Green G et al (2009) Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature 457:599–602. doi:10.1038/nature07586 PubMedCrossRefGoogle Scholar
  93. Van Raamsdonk CD, Griewank KG, Crosby MB et al (2010) Mutations in GNA11 in uveal melanoma. N Engl J Med 363:2191–2199. doi:10.1056/NEJMoa1000584 PubMedCrossRefGoogle Scholar
  94. Viros A, Fridlyand J, Bauer J et al (2008) Improving melanoma classification by integrating genetic and morphologic features. PLoS Med 5:e120PubMedCrossRefGoogle Scholar
  95. Wang Y, Becker D (1997) Antisense targeting of basic fibroblast growth factor and fibroblast growth factor receptor-1 in human melanomas blocks intratumoral angiogenesis and tumor growth. Nat Med 3:887–893PubMedCrossRefGoogle Scholar
  96. Wellbrock C, Gomez A, Schartl M (1997) Signal transduction by the oncogenic receptor tyrosine kinase Xmrk in melanoma formation of Xiphophorus. Pigment Cell Res 10:34–40PubMedCrossRefGoogle Scholar
  97. Willmore-Payne C, Holden JA, Hirschowitz S, Layfield LJ (2006) BRAF and c-kit gene copy number in mutation-positive malignant melanoma. Hum Pathol 37:520–527PubMedCrossRefGoogle Scholar
  98. Wong CW, Fan YS, Chan TL et al (2005) BRAF and NRAS mutations are uncommon in melanomas arising in diverse internal organs. J Clin Pathol 58:640–644PubMedCrossRefGoogle Scholar
  99. Wyman K, Atkins MB, Prieto V et al (2006a) Multicenter Phase II trial of high-dose imatinib mesylate in metastatic melanoma: significant toxicity with no clinical efficacy. Cancer 106:2005–2011PubMedCrossRefGoogle Scholar
  100. Wyman K, Kelley M, Puzanov I et al (2006b) Phase II study of erlotinib given daily for patients with metastatic melanoma (MM). J Clin Oncol 24Google Scholar
  101. Yarden Y (2001) The EGFR family and its ligands in human cancer. Signalling mechanisms and therapeutic opportunities. Eur J Cancer 37(Suppl 4):S3–S8PubMedCrossRefGoogle Scholar
  102. Zhou XP, Gimm O, Hampel H et al (2000) Epigenetic PTEN silencing in malignant melanomas without PTEN mutation [In process citation]. Am J Pathol 157:1123–1128PubMedCrossRefGoogle Scholar
  103. Zsebo KM, Williams DA, Geissler EN et al (1990) Stem cell factor is encoded at the SI locus of the mouse and is the ligand for the c-kit tyrosine kinase receptor. Cell 63:213–224. doi:10.1016/0092-8674(90)90302-U PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  1. 1.University of CaliforniaSan FranciscoUSA
  2. 2.Memorial Sloan-Kettering Cancer CenterNew YorkUSA

Personalised recommendations