Activity of a novel Aurora kinase inhibitor against the T315I mutant form of BCR‐ABL: In vitro and in vivo studies

Despite promising results from clinical studies of ABL kinase inhibitors, a challenging problem that remains is the T315I mutation against which neither nilotinib nor dasatinib show significant activity. In the present study, we investigated the activity of a novel Aurora kinase inhibitor, VE‐465, against leukemia cells expressing wild‐type BCR‐ABL or the T315I mutant form of BCR‐ABL. We observed a dose‐dependent reduction in the level of BCR‐ABL autophosphorylation in VE‐465‐treated cells. Exposure to the combination of VE‐465 and imatinib exerted an enhanced apoptotic effect in K562 cells. Combined treatment with VE‐465 and imatinib caused more attenuation of the levels of phospho‐AKT and c‐Myc in K562 cells. Further, the isobologram indicated the synergistic effect of simultaneous exposure to VE‐465 and imatinib in K562 cells. To assess the in vivo efficacy of VE‐465, athymic nude mice were injected intravenously with BaF3 cells expressing wild‐type BCR‐ABL or the T315I mutant form. The vehicle‐treated mice died of a condition resembling acute leukemia by 28 days; however, nearly all mice treated with VE‐465 (75 mg/kg, twice daily; intraperitoneally for 14 days) survived for more than 56 days. Histopathological analysis of vehicle‐treated mice revealed infiltration of the spleen. In contrast, histopathological analysis of organs from VE‐465‐treated mice demonstrated normal tissue architecture. Taken together, the present study shows that VE‐465 exhibits a desirable therapeutic index that can reduce the in vivo growth of T315I mutant form and wild‐type BCR‐ABL‐expressing cells in an efficacious manner. (Cancer Sci 2008; 99: 1251–1257)