Dasatinib (BMS-354825), a novel multi-targeted kinase inhibitor that blocks tumor cell migration and invasion, is a promising therapeutic agent for metastatic prostate cancer

3797 SRC family kinases (SFKs) are currently being investigated as targets for treatment strategies in various cancers. Dasatinib (BMS-354825) is a novel, highly potent, oral, multi-targeted kinase inhibitor of BCR-ABL and SFKs. Dasatinib has been shown to inhibit growth of BCR-ABL-dependent chronic myeloid leukemia xenografts in nude mice and has been efficacious and well tolerated in a Phase I clinical trial of patients with imatinib-resistant or -intolerant CML. Dasatinib has also demonstrated activity against cultured human prostate and breast cancer cells; however, the molecular mechanism by which dasatinib acts on epithelial tumor cells remains unknown. In this study, we show that dasatinib blocks the kinase activities of the SFKs, Lyn and Src in human prostate cancer cells at low nanomolar concentrations. Moreover, focal adhesion kinase (FAK), which has been shown to be elevated in epithelial tumors, and Crk-associated substrate (p130 CAS ) signaling downstream of SFKs are also inhibited at similar dasatinib concentrations. Consistent with inhibition of these signaling pathways, dasatinib suppresses cell adhesion, migration, and invasion of prostate cancer cells at low nanomolar concentrations. Therefore, dasatinib has potential as a therapeutic agent for metastatic prostate cancers harboring activated SFK and FAK signaling. Phase I clinical evaluation of dasatinib in a variety of solid tumors, including prostate cancer, is currently ongoing.