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Metformin Synergizes with Gilteritinib in Treating FLT3-mutated Leukemia Via Targeting PLK1 Signaling

Abstract

Fms-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.

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PMID: 39596291 PMC: 11594995. DOI: 10.3390/ijms252212219.

References
1.
Satterwhite L . Metformin Extended-Release Oral Solution. Clin Diabetes. 2021; 39(2):226-227. PMC: 8061547. DOI: 10.2337/cd21-0009. View

2.
Weichert W, Denkert C, Schmidt M, Gekeler V, Wolf G, Kobel M . Polo-like kinase isoform expression is a prognostic factor in ovarian carcinoma. Br J Cancer. 2004; 90(4):815-21. PMC: 2410182. DOI: 10.1038/sj.bjc.6601610. View

3.
Mizuki M, Fenski R, Halfter H, Matsumura I, Schmidt R, Muller C . Flt3 mutations from patients with acute myeloid leukemia induce transformation of 32D cells mediated by the Ras and STAT5 pathways. Blood. 2000; 96(12):3907-14. View

4.
Subramanian A, Tamayo P, Mootha V, Mukherjee S, Ebert B, Gillette M . Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005; 102(43):15545-50. PMC: 1239896. DOI: 10.1073/pnas.0506580102. View

5.
Foretz M, Guigas B, Bertrand L, Pollak M, Viollet B . Metformin: from mechanisms of action to therapies. Cell Metab. 2014; 20(6):953-66. DOI: 10.1016/j.cmet.2014.09.018. View