Metformin synergizes with gilteritinib in treating FLT3-mutated leukemia via targeting PLK1 signaling

Highlights•Metformin substantially sensitizes FLT3-mutated AML cells to gilteritinib in vitro•Metformin synergizes with gilteritinib in treating FLT3-ITD AML in vivo•Metformin and gilteritinib cooperatively target PLK1/STAT5-ERK-mTOR in FLT3-ITD AML•Metformin plus TKI offers a potent and cost-effective therapy for FLT3-ITD AMLSummaryFms-like tyrosine kinase 3 (FLT3) mutations, present in over 30% of acute myeloid leukemia (AML) cases and dominated by FLT3-internal tandem duplication (FLT3-ITD), are associated with poor outcomes in patients with AML. While tyrosine kinase inhibitors (TKIs; e.g., gilteritinib) are effective, they face challenges such as drug resistance, relapse, and high costs. Here, we report that metformin, a cheap, safe, and widely used anti-diabetic agent, exhibits a striking synergistic effect with gilteritinib in treating FLT3-ITD AML. Metformin significantly sensitizes FLT3-ITD AML cells (including TKI-resistant ones) to gilteritinib. Metformin plus gilteritinib (low dose) dramatically suppresses leukemia progression and prolongs survival in FLT3-ITD AML mouse models. Mechanistically, the combinational treatment cooperatively suppresses polo-like kinase 1 (PLK1) expression and phosphorylation of FLT3/STAT5/ERK/mTOR. Clinical analysis also shows improved survival rates in patients with FLT3-ITD AML taking metformin. Thus, the metformin/gilteritinib combination represents a promising and cost-effective treatment for patients with FLT3-mutated AML, particularly for those with low income/affordability.Graphical abstract