Effect of dual inhibition of histone deacetylase and phosphatidylinositol-3 kinase in Philadelphia chromosome-positive leukemia cells.

Purpose: ABL tyrosine kinase inhibitors (TKIs) have demonstrated potency in the treatment of chronic myeloid leukemia (CML) patients. However, resistance to ABL TKIs can develop in CML patients due to BCR-ABL point mutations. Furthermore, CUDC-907 is an oral inhibitor of class I phosphoinositide 3-kinase (PI3K) as well as class I and II histone deacetylase (HDAC) enzymes.

Methods: In this study, we evaluated the effect of combination therapy of CUDC-907 and ABL TKIs, using BCR-ABL-positive cell lines and primary samples.

Results: CUDC-907 treatment for 72 h resulted in cell growth inhibition. Over the same period, an increase in histone acetylation and both caspase three and poly (ADP-ribose) polymerase (PARP) enzyme activity was observed. When ABL TKI treatment and CUDC-907 treatment were combined, significantly greater cytotoxicity was observed. Moreover, combined oral therapy with ponatinib (20 mg/kg/day) and CUDC-907 (30 mg/kg/day) greatly inhibited tumor growth compared to each drug alone. Lastly, CUDC-907 treatment also inhibited the growth of Ba/F3 ponatinib-resistant cells, K562 nilotinib-resistant cells, and T315I mutant primary samples.

Conclusion: Taken together, our results indicate that administration of CUDC-907, a dual PI3K and HDAC inhibitor, may be an effective strategy against ABL TKI-resistant cells, including cells harboring the T315I mutation. Moreover, CUDC-907 may enhance the cytotoxic effects of ABL TKI when a combined treatment strategy is used against Philadelphia chromosome-positive leukemia cells.