title: c-KIT signaling as the driving oncogenic event in sub-groups of melanomas.
abstract: As we enter the era of targeted therapy for melanoma, attempts are being made to sub-group tumors on the basis of their driving oncogenic mutations, with the hope of developing truly personalized therapeutic regimens. c-KIT is a receptor tyrosine kinase whose aberrant activation is implicated in the progression of gastrointestinal stromal tumors and some acute myeloid leukemias. The role of c-KIT signaling in melanoma has been controversial; although c-KIT activity is critical to melanocyte development, its expression tends to be lost in most melanomas. Some reports have even shown that the re-expression of c-KIT induces apoptosis in melanoma cell lines. The recent publication of work showing the presence of activating c-KIT mutations in acral and mucosal melanomas, as well as melanomas arising on skin with chronic sun damage, has renewed interest in c-KIT signaling in melanoma. Recent work from our own laboratory has further identified melanomas with constitutive c-KIT signaling activity resulting from c-KIT receptor overexpression. Although the initial clinical trials of the c-KIT inhibitor imatinib mesylate in melanoma were negative, some dramatic responses have been seen in patients with very high c-KIT expression and/or documented activating mutations, fostering the belief that focused studies in patients selected on the basis of c-KIT mutational status will yield more encouraging results. The current review discusses the role of c-KIT signaling in melanoma progression and how this new information can be applied to the targeted therapy of melanoma.
authors.affiliation: The Comprehensive Melanoma Research Center and the Department of Cutaneous Oncology, The Moffitt Cancer Center, Tampa, FL, USA. keiran.smalley@moffitt.org
authors.forename: Keiran S M
authors.initials: KS
authors.lastname: Smalley
authors.forename: Vernon K
authors.initials: VK
authors.lastname: Sondak
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Weber
mesh_terms: D000818:Animals; D001549:Benzamides; D006801:Humans; D000068877:Imatinib Mesylate; D008544:Melanocytes / Q000166:cytology / Q000201:enzymology; D008545:Melanoma / Q000145:classification / Q000201:enzymology* / Q000209:etiology* / Q000235:genetics; D008546:Melanoma, Experimental / Q000145:classification / Q000201:enzymology / Q000209:etiology / Q000235:genetics; D051379:Mice; D008954:Models, Biological; D009154:Mutation; D010879:Piperazines / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D019009:Proto-Oncogene Proteins c-kit / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000627:therapeutic use; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000235:genetics / Q000378:metabolism; D014604:Uveal Neoplasms / Q000201:enzymology / Q000209:etiology / Q000235:genetics
chemical_list: D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D019089:Stem Cell Factor; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit