Clinical Development of Src Family Kinase Inhibitors in Malignant Melanoma

摘要

Currently available systemic therapies for malignant melanoma are unsatisfactory and there is an urgent needfor effective and well tolerated drugs for use in both early and advanced disease. The Src family of cytoplasmic tyrosinekinases (SFKs) have been implicated in the regulation of many of the hallmarks of malignancy making them attractivetargets 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 IItrials in patients with advanced melanoma are now planned in the USA and Europe. Here we discuss the rationale for, andchallenges facing, the successful development of SFK inhibitors in melanoma. Furthermore, as dasatinib is also a potentinhibitor of the receptor tyrosine kinase (RTK), c-Kit, we reconsider the utility of targeting this kinase in the light of recentmolecular epidemiological data.