The Src family kinase inhibitor dasatinib (BMS-354825) blocks migration and invasion of human melanoma cells

3248 Dasatinib (BMS-354825) is a potent inhibitor of multiple oncogenic protein kinases that has been approved by the FDA and European Union in all stages of CML and Ph+ ALL resistant or intolerant to prior therapy. On the basis of oral bioavailability, in vivo activity and pharmacokinetic profile, as well as its low toxicity, dasatinib has advanced to early-phase clinical trials for solid tumors harboring activated Src kinase. Although Src family kinases (SFK) are currently being investigated as potential targets for treatment strategies in various cancers, the effect of dasatinib on human melanoma cells has not been investigated in detail. In this study, we show that dasatinib blocks migration and invasion of human melanoma cells without affecting proliferation and survival. Moreover, dasatinib completely inhibits SFK kinase activity at low nanomolar concentrations in all 8 human melanoma cell lines examined. In addition, two known downstream targets of SFKs, focal adhesion kinase (FAK) and Crk-associated substrate (p130CAS), are inhibited with similar concentrations and kinetics. Consistent with inhibition of these signaling pathways and invasion, we show that dasatinib also down-regulates expression of matrix metalloproteinase-9 (MMP-9). We also provide evidence that dasatinib directly inhibits kinase activity of the EphA2 receptor tyrosine kinase, which is overexpressed and/or overactive in many solid tumors including melanoma. Since SFK/FAK/p130CAS as well as EphA2 signaling pathways are involved in tumor progression, our findings suggest that dasatinib is a promising agent for preventing melanoma metastasis.