Clinical Development of Src Family Kinase Inhibitors in Malignant Melanoma

Abstract

Currently available systemic therapies for malignant melanoma are unsatisfactory and there is an urgent need for effective and well tolerated drugs for use in both early and advanced disease. The Src family of cytoplasmic tyrosine kinases (SFKs) have been implicated in the regulation of many of the hallmarks of malignancy making them attractive targets in solid tumours including melanoma. The first generation of selective SFK inhibitors to enter the clinic (AZD0530, dasatinib, bosutinib) have demonstrated safety, tolerability and target modulation in phase I trials. Phase II trials in patients with advanced melanoma are now planned in the USA and Europe. Here we discuss the rationale for, and challenges facing, the successful development of SFK inhibitors in melanoma. Furthermore, as dasatinib is also a potent inhibitor of the receptor tyrosine kinase (RTK), c-Kit, we reconsider the utility of targeting this kinase in the light of re- cent molecular epidemiological data.