Strategies to overcome resistance to FMS-like tyrosine kinase 3 (FLT3)-targeted therapy in acute myeloid leukemia (AML) are urgently needed. We identify autophagy as one of the resistance mechanisms, induced by hypoxia and the bone marrow (BM) microenvironment via Bruton’s tyrosine kinase (BTK) activation. Suppressing autophagy/BTK sensitized FLT3-mutated AML to FLT3 inhibitor-induced apoptosis. Further, co-targeting FLT3/BTK/Aurora kinases (AURKs) with a novel multi-kinase inhibitor CG-806 (luxeptinib) induced profound apoptosis induction in FLT3-mutated AML by co-suppressing FLT3/BTK, antagonizing autophagy, and causing leukemia cell death in FLT3 wild-type AML by AURK-mediated G2/M arrest and polyploidy, in addition to FLT3 inhibition. Thus, CG-806 exerted profound anti-leukemia activity against AMLs regardless of FLT3 mutation status. CG-806 further significantly reduced AML burden and extended survival in an in vivo PDX leukemia murine model of FLT3 inhibitorresistant FLT3-ITD/TKD double mutant primary AML. Taken together, CG-806 exerts a unique mechanistic action and pre-clinical activity, suggesting further development in FLT3 wild-type and mutant AML.
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