Resensitizing the Imatinib-Resistant Chronic Myeloid Leukemia through Reshaping the Glucose Mtabolism By Insulin Sensitizer

Tyrosine kinase inhibitor (TKI) such as Imatinib (IM) is the preferred treatment for Chronic Myeloid Leukemia (CML). However, TKIs resistant generate a significant challenge to disease management. Activation of key signaling pathways, cell cycle disruptions, abnormal epigenetic events, aberrant stem cell niche microenvironments, and metabolic shifts had been reported to be associated with TKI resistance. We detected the increased glucose uptake and lactate production in high dose IM-induced CML resistant cells. Chiglitazar (Chi), a novel Insulin Sensitizer, reduced the glucose metabolism in stem-like cell of Acute Myeloid Leumia (AML) according to our previous study. This inspired us to test its therapeutic effect in CML management. Cell proliferation, cell cycle distribution, and apoptosis results showed the cell killing effect when combined with IM but not Chi-only in IM-resistant CML cells. RNA-Seq and western blotting showed the Chi reducing the glucose uptake, reducing lactate production, and resensitizing the IM-resistant CML cells through the PPARγ/mTOR/PKM2 pathway. Further, we introduced shPPARγ to knockdown PPARγ in IM-resistant cells after Chi treatment for 24h. Downregulation of PPARγ significantly redued the apoptosis-induction effect when IM-resistant cells treated with IM and Chi combined treatment. Moreover, mTOR activator (MHY1485) could mimic the the synergistic effect of Chi and IM combination treatment. Finally, in vivo data confirmed the anti-leukemic effect of Chi and IM combination regimen in CDX (cell derived xnograft) models. Thus, we concluded that combining Chi and IM serves as a potential thrapeutic regimen in CML clinical management.