MDV3100 is an androgen receptor antagonist

by Selleckchem | Jan 15 2013

Increased protein levels and kinase activities of Src family kinases have been observed in a wide diversity of human cancers, including melanoma, breast, ovarian, and lung cancer . The prototype SFK is c-Src, MDV3100 which is a protein tyrosine kinase from which the oncogenic viral Src is derived . An abundance of evidence suggests that a primary role for SFKs, in particular c-Src, is to regulate cell adhesion, motility and invasion . During tumor cell transendothelial migration , a critcal step in cancer metastasis, Src becomes activated at the heterotypic contact between the transmigrating melanoma cell and the neighboring endothelial cells . SFKs can also promote proliferation and survival in response to signaling initiated by binding of mitogenic growth factors to their cognate receptors . In addition, there is growing evidence that SFKs have a critical role in tumor angiogenesis at least in part through regulation of expression of angiogenic factors such as IL-8 and VEGF . Dasatinib is a novel, oral, multi-targeted, kinase inhibitor of BCR-ABL, c-KIT, PDGFR, and SFKs . The anti-tumor potency of dasatinib has been demonstrated in early- and late-phase clinical trials for chronic myelogeneous leukemia .Dasatinib recently has been approved by the FDA and European Union for treatment of all stages of CML in patients with 17-AAG imatinib-resistant/-intolerant disease. Clinical trials are currently ongoing for evaluation of dasatinib in treatment of solid tumors. Because of the myriad of critical roles of SFKs in basic biological processes, molecularly targeted smallmolecule inhibitors of SFKs could induce numerous biological responses. Importantly, 17-DMAG the therapeutic potential of dasatinib in solid tumors, including melanoma, remains to be fully determined. However, the development of Src transgenic mice and the effects of activated Src on tumor formation and promotion in these animal models, including that of the skin, further suggest a critical role of SFKs in solid tumors, including melanoma . Recently, clinical trial data were presented that indicate the potential utility of dasatinib in treatment of solid tumors such as metastatic hormone-refractory prostate cancer . We investigated the effect of dasatinib on eight human melanoma cell lines, all of which harbor constitutive SFK activity as measured by tyrosyl A66 phosphorylation of their autophosphorylation site.Here we show that treatment of melanoma cells with low nanomolar concentrations of dasatinib completely abolishes SFK autophosphorylation activity in cells. Moreover, blockade of SFK activity correlates with greatly reduced phosphorylation of the known SFK downstream targets, focal adhesion kinase and Crk-associated substrate . Elevated FAK activity in human melanoma was shown previously to promote tumor cell invasion and migration . Consistent with this role of FAK activity ABT-263 in melanoma, dasatinib-mediated inhibition of the SFK/FAK signaling pathway completely abolishes migration and invasion of melanoma cells. Our findings suggest that SFK signaling is important for migration and invasion but not proliferation and survival of melanoma cells.