Seiichi Okabe1, Yuko Tanaka2, Mitsuru Moriyama2, Akihiko Gotoh2. 1. Department of Hematology, Tokyo Medical University, 6-7-1 Nishi-shinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan. okabe@tokyo-med.ac.jp. 2. Department of Hematology, Tokyo Medical University, 6-7-1 Nishi-shinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan.
Abstract
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.
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.
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