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.
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References
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
Ahmed NU, Ueda M, Ito A et al (1997) Expression of fibroblast growth factor receptors in naevus-cell naevus and malignant melanoma. Melanoma Res 7:299–305
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
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 60:1968–1973
Bastian BC, LeBoit PE, Pinkel D (2000b) Mutations and copy number increase of HRAS in Spitz nevi with distinctive histopathological features. Amn J Pathol 157:967–972
Bastian BC, Olshen AB, LeBoit PE, Pinkel D (2003) Classifying melanocytic tumors based on DNA copy number changes. Am J Pathol 163:1765–1770
Bauer J, Curtin JA, Pinkel D, Bastian BC (2007) Congenital melanocytic nevi frequently harbor NRAS mutations but no BRAF mutations. J Invest Dermatol 127:179–182
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
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
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 114:277–280
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 88:4671–4674
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
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):9001
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
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
Curtin JA, Fridlyand J, Kageshita T et al (2005) Distinct sets of genetic alterations in melanoma. N Engl J Med 353:2135–2147
Curtin JA, Busam K, Pinkel D, Bastian BC (2006) Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol 24:4340–4346
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
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
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
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 28
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 62:7335–7342
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
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
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 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
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
Ehlers JP, Harbour JW (2006) Molecular pathobiology of uveal melanoma. Int Ophthalmol Clin 46:167–180
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
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
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
Gogas HJ, Kirkwood JM, Sondak VK (2007) Chemotherapy for metastatic melanoma: time for a change? Cancer 109:455–464. doi:10.1002/cncr.22427
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
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 57:3660–3663
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 107:1611–1619
Halaban R, Kwon BS, Ghosh S et al (1988b) bFGF as an autocrine growth factor for human melanomas. Oncogene Res 3:177–186
Hodi FS, Friedlander P, Corless CL et al (2008) Major response to imatinib mesylate in KIT-mutated melanoma. J Clin Oncol 26:2046–2051
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
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 28
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
Jemal A, Siegel R, Ward E et al (2009) Cancer statistics, 2009. CA Cancer J Clin 59:225–249. doi:10.3322/caac.20006
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 13:211–217
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
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 14:207–210
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 125:2915–2923
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 94:67–78
Lassam N, Bickford S (1992) Loss of C-Kit expression in cultured melanoma-cells. Oncogene 7:51–56
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
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
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):492–495
Ma XM, Blenis J (2009) Molecular mechanisms of mTOR-mediated translational control. Nat Rev Mol Cell Biol 10:307–318. doi:10.1038/nrm2672
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
Maldonado JL, Fridlyand J, Patel H et al (2003) Determinants of BRAF mutations in primary melanoma. J Natl Cancer Inst 95:1878–1890
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
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
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 18:12–21
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
Montone KT, Belle P, Elder DE (1997) Proto-oncogene c-kit expression in malignant melanoma: protein loss with tumor progression. Mod Pathol 10(9):939–944
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 52:197–201
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
Noonan FP, Otsuka T, Bang S et al (2000) Accelerated ultraviolet radiation-induced carcinogenesis in hepatocyte growth factor/scatter factor transgenic mice. Cancer Res 60:3738–3743
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 25
Padua RA, Barrass NC, Currie GA (1985) Activation of N-ras in a human melanoma cell line. Mol Cell Biol 5:582–585
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
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
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 130:80–86
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
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
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
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 436:487–493
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
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 92:374–381
Sauter ER, Yeo UC, Von Stemm A et al (2002) Cyclin D1 is a candidate oncogene in cutaneous melanoma. Cancer Res 62:3200–3206
Serrano M, Lee H, Chin L et al (1996) Role of the INK4a locus in tumor suppression and cell mortality. Cell 85:27–37
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
Sherr CJ, Roberts JM (1999) CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 13:1501–1512
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
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 93:436–446
Sousa SF, Fernandes PA, Ramos MJ (2008) Farnesyltransferase inhibitors: a detailed chemical view on an elusive biological problem. Curr Med Chem 15:1478–1492
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 40:19–24
Stahl JM, Sharma A, Cheung M et al (2004) Deregulated Akt3 activity promotes development of malignant melanoma. Cancer Res 64:7002–7010
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
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 94:701–706
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
Trent JM, Meyskens FL, Salmon SE et al (1990) Relation of cytogenetic abnormalities and clinical outcome in metastatic melanoma. N Engl J Med 322:1508–1511
Tsao H, Zhang X, Fowlkes K, Haluska FG (2000) Relative reciprocity of NRAS and PTEN/MMAC1 alterations in cutaneous melanoma cell lines. Cancer Res 60:1800–1804
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 122:337–341
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 130:320–324
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
Ugurel S, Hildenbrand R, Zimpfer A et al (2005) Lack of clinical efficacy of imatinib in metastatic melanoma. Br J Cancer 92:1398–1405
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 36:151–158
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
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
Viros A, Fridlyand J, Bauer J et al (2008) Improving melanoma classification by integrating genetic and morphologic features. PLoS Med 5:e120
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 3:887–893
Wellbrock C, Gomez A, Schartl M (1997) Signal transduction by the oncogenic receptor tyrosine kinase Xmrk in melanoma formation of Xiphophorus. Pigment Cell Res 10:34–40
Willmore-Payne C, Holden JA, Hirschowitz S, Layfield LJ (2006) BRAF and c-kit gene copy number in mutation-positive malignant melanoma. Hum Pathol 37:520–527
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 58:640–644
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 106:2005–2011
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 24
Yarden Y (2001) The EGFR family and its ligands in human cancer. Signalling mechanisms and therapeutic opportunities. Eur J Cancer 37(Suppl 4):S3–S8
Zhou XP, Gimm O, Hampel H et al (2000) Epigenetic PTEN silencing in malignant melanomas without PTEN mutation [In process citation]. Am J Pathol 157:1123–1128
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
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Daud, A., Bastian, B.C. (2010). Beyond BRAF in Melanoma. In: Mellinghoff, I., Sawyers, C. (eds) Therapeutic Kinase Inhibitors. Current Topics in Microbiology and Immunology, vol 355. Springer, Berlin, Heidelberg. https://doi.org/10.1007/82_2011_163
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