mTOR inhibition by AZD2014 alleviates BCR::ABL1 independent imatinib resistance through enhancing autophagy in CML resistant cells.

ABSTRACT

Chronic myeloid leukemia (CML) is a common hematopoietic malignancy in adults. Great progress has been made in CML therapy with imatinib. However, resistance to imatinib may occur during treatment. BCRABL1 dependent imatinib resistance has been well resolved with more potent tyrosine kinase inhibitors, but BCRABL1 independent resistance still remains to be resolved. This study is devoted to find novel targets for BCRABL1 independent imatinib-resistant patients. It is reported BCRABL1 independent resistance is mainly related to the activation of alternative survival pathway, and mTOR is an important regulator for cell growth especially in tumor cells. Hence, we explored the role of mTOR in BCRABL1 independent resistance, the possibility of mTOR to be a therapeutic target for imatinib resistant patients and the related mechanism. We found mTOR was upregulated in imatinib-resistant cells. mTOR inhibition by AZD2014 led to growth inhibition and synergized with imatinib in apoptosis induction in K562/G01. AZD2014 exerted its anti-leukemia effect through enhancing autophagy. mTOR signal pathway is poorly inhibited by imatinib and AZD2014 shows little effect on BCRABL1 signal pathway, which indicates that mTOR is involved in imatinib resistance via a BCRABL1 independent manner. Taken together, mTOR represents a potential target to overcome BCRABL1 independent imatinib resistance.