Simultaneous Targeting of Aurora Kinases and Bcr-Abl by the Small Molecule Inhibitor PHA-739358 Is Effective in Imatinib-Resistant Mutations Including T315I.

The emergence of resistance to Imatinib (IM) mediated by mutations in the BCR-ABL domain became a major challenge in the treatment of chronic myeloid leukemia (CML). Second generation Bcr-Abl inhibitors overcome most mutations except T315I, a frequent cause of clinical resistance, emphasising the importance of developing alternative therapeutic strategies. Here, we report studies performed with a novel small molecule inhibitor, PHA-739358, which selectively targets Bcr-Abl and Aurora kinases. PHA-739358 exhibited strong antiproliferative and pro-apoptotic activity against a broad panel of human BCR-ABL positive and negative cell lines and against mouse BaF3 cells ectopically expressing wild type (wt) or IM-resistant BCR-ABL mutants, including T315I. Pharmacological synergism of IM and PHA-739358 was observed in leukemia cell lines with low-level resistance to IM, whereas no synergistic effects were observed in BCR-ABL negative or highly IM resistant T315I mutated cells. Treatment with PHA-739358 significantly decreased phosphorylation of histone H3-(Ser10), a marker of Aurora B activity and of the small adaptor protein CrkL, an accepted down-stream target of Bcr-Abl. Hence, PHA-739358 acts via combined inhibition of Bcr-Abl and Aurora kinases. Moreover, strong antiproliferative effects of PHA-739358 were observed in CD34+ cells derived from newly diagnosed CML patients and from IM-resistant individuals in chronic phase or blast crisis including those harbouring a T315I mutation. Thus, PHA-739358 represents a promising new strategy for treatment of IM resistant BCR-ABL positive leukemias, including those harbouring the T315I mutation. Clinical trials investigating this compound in IM-resistant CML have recently been initiated.