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BMS-354825 is an ATP-competitive, small molecule tyrosine kinase inhibitor that suppresses Src family kinases, EphA2, Abl, c-kit, and PDGFR activity at sub-nanomolar concentrations. Src activation in malignant cells induces pleiotropic effects that include transformation, increased proliferation, enhanced survival, stimulation of angiogenesis, and changes in motility. Src is overexpressed and activated in epithelial tumors, including HNSCC and NSCLC. Levels of expression or activation correlate with disease progression, suggesting that Src inhibition may have therapeutic activity in these diseases. HNSCC and NSCLC incubation with clinically relevant BMS-354825 concentrations has multiple biological effects that appear to be mediated through Src and/or EphA2 inhibition. BMS-354825 inhibited migration in all cell lines and induced cell cycle arrest (block in the G1 to S transition) and subsequent apoptosis in highly sensitive cell lines. The effects on migration correlate with inhibition of Src and downstream mediators of adhesion (FAK, p130, paxillin), while cell cycle effects and apoptosis correlate with inhibition of AKT, induction of p27, and de-phosphorylation of Rb. BMS-354825 also induced morphology changes that were integrin-dependent, consistent with an upstream role for Src in regulation of focal adhesion complexes. Additional studies are focused on the effects Src inhibition on angiogenesis and metastasis in animal models of aerodigestive tract tumors. BMS-354825 may have therapeutic activity against HNSCC and NSCLC.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]