CDK5/CAMK2-DRP1-AMPK-Mediated Mitochondrial Fission is Required for Imatinib Resistance of CML Cells

Background: In chronic myeloid leukemia (CML), resistance to tyrosine kinase inhibitors (TKIs) is still a serious clinical challenge, especially in the context of multi-resistance BCR-ABL mutations, such as T315I. Increasing evidence has demonstrated that mitochondrial fission plays an important role in cancer stem cell maintenance and drug resistance. Therefore, as a vital fission-related protein, DRP1 serves as a novel target for cancer treatment. However, whether DRP1 inhibition could overcome imatinib resistance in CML remains unknown. Methods: We used bioinformatic analysis and a confocal microscopy experimental approach to investigate whether mitochondrial fission could be involved in drug resistance in CML. Next, we applied biological and metabolic detection methods to reveal the roles of DPR1 in autophagy, apoptosis, and mitochondrial respiration in CML cells and determine whether coupling imatinib with DRP1 inhibition has a synergetic anti-leukemic effect on both drug-sensitive and drug-resistant CML cells. Results: : Resistant CML cells displayed fragmented mitochondria and were accompanied by overexpression of active DRP1 compared with their sensitive counterparts. Furthermore, blocking DRP1 decreased mitochondrial respiration via the CDK5/CAMK2-DRP1-AMPK signaling pathway. Additionally, DRP1 inhibition perturbed the balance between mitochondrial-dependent apoptosis and autophagy, which led to cell death. Finally, combination treatment with imatinib and DRP1 inhibition exhibited a synergetic anti-leukemic effect on both drug-sensitive and drug-resistant CML cells (including CML cells carrying T315I mutation) in in vitro or in vivo experiments. Conclusions: : Combination treatment with imatinib and DRP1 inhibition may represent a promising strategy to overcome CML drug resistance.