c-KIT signaling as the driving oncogenic event in sub-groups of melanomas

Keiran S.M. Smalley, Vernon K. Sondak and Jeffrey S. Weber

The Comprehensive Melanoma Research Center and the Department of Cutaneous Oncology, The Moffitt Cancer Center,and the Department of Oncologic Sciences, University of South Florida College of Medicine, Tampa, FL, USA.

Offprint requests to: Keiran S.M. Smalley, 12902 Magnolia Drive, Tampa, FL 33612, USA. e-mail: keiran.smalley@moffitt.org


Summary. 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. Histol Histopathol 24, 643-650 (2009)

Key words: c-KIT, Melanoma, Inatinib, BRAF, Ocular melanoma

DOI: 10.14670/HH-24.643