Combination therapy with copanlisib and ABL tyrosine kinase inhibitors against Philadelphia chromosome-positive resistant cells
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Seiichi Okabe1, Tetsuzo Tauchi1, Yuko Tanaka1, Juri Sakuta1, Kazuma Ohyashiki1
1Department of Hematology, Tokyo Medical University, Tokyo, Japan
Seiichi Okabe, email: [email protected]
Keywords: chronic myeloid leukemia, phosphoinositide 3-kinase, ABL tyrosine kinase inhibitor, feeder cell
Received: May 06, 2016 Accepted: June 30, 2016 Published: July 14, 2016
ABL tyrosine kinase inhibitor (TKI) therapy has improved the survival of patients with Philadelphia (Ph) chromosome-positive leukemia. However, ABL TKIs cannot eradicate leukemia stem cells. Therefore, new therapeutic approaches for Ph-positive leukemia are needed. Aberrant activation of phosphoinositide 3-kinase (PI3K) signaling is important for the initiation and maintenance of human cancers. Copanlisib (BAY80-6946) is a potent inhibitor of PI3Kα and PI3K-δ. Here we investigated the efficacy of combination therapy of copanlisib with an ABL TKI (imatinib, nilotinib, or ponatinib) using BCR-ABL-positive cells. Although the effects of the ABL TKI treatment were reduced in the presence of the feeder cell line, HS-5, copanlisib inhibited cell growth. Upon combining ABL TKI and copanlisib, cell growth was reduced. Ponatinib and copanlisib combined therapy reduced tumor volume and increased survival in mouse allograft models, respectively. These results indicate that the PI3Kα and -δ inhibitors overcame the chemoprotective effects of the feeder cells and enhanced ABL TKI cytotoxicity. Thus, co-treatment with ABL TKI and copanlisib may be a powerful strategy against ABL TKI-resistant cells, including those harboring the related T315I mutation.
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