Targeting autophagy with hydroxychloroquine potentiates ponatinib- and axitinib-induced cell death in BCR-ABL T315I-containing CML

Purpose Because of the dose-dependent increased risk of cardiovascular events we tried to lower the dose of ponatinib without reducing its efficacy in the treatment of BCR-ABL T315I-containing CML. Combination with hydroxychloroquine can enhance the efficiency of ponatinib and axitinib through autophagy inhibition in CML cell with T315I. Methods Cell viability, cell cycle, cellular senescence, formation of cell clones and apoptosis assay were taken to test the efficiency of medicine. Lentiviral vectors containing shRNA was used to block autophagy and to verify the mechanism of the medicine. Establish tumor models in nude mice, and verify the experimental results in vivo. Results ponatinib and axitinib killed 32Dp210-T315I cells as well as inducing autophagy, which promoted their survival under pressure from TKIs. By inhibiting autophagy, HCQ enhanced the killing effect of ponatinib and axitinib on 32Dp210-T315I cells. In vivo HCQ also enhanced the killing effect of axitinib on 32Dp210-T315I cells. Conclusion HCQ combined with ponatinib may be a new strategy for treating CML and ALL that harbor the T315I mutation. Thus, this combination may make it possible to reduce the dose of ponatinib and reduce its side effects without compromising efficacy.