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Ref Type Journal Article
PMID (39019012)
Authors Chen M, Shen C, Chen Y, Chen Z, Zhou K, Chen Y, Li W, Zeng C, Qing Y, Wu D, Xu C, Tang T, Che Y, Qin X, Xu Z, Wang K, Leung K, Sau L, Deng X, Hu J, Wu Y, Chen J
Title Metformin synergizes with gilteritinib in treating FLT3-mutated leukemia via targeting PLK1 signaling.
Journal Vol Issue Date Pages Journal Short Title
Cell reports. Medicine 5 7 2024 Jul 16 101645 Cell Rep Med
URL
Abstract Text 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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FLT3 exon 14 ins acute myeloid leukemia sensitive Gilteritinib + Metformin Preclinical - Cell line xenograft Actionable In a preclinical study, the combination of Xospata (gilteritinib) and Glucophage (metformin) synergistically inhibited viability and induced apoptosis and cell cycle arrest in acute myeloid leukemia cell lines and patient-derived cells harboring a FLT3-ITD mutation in culture, and reduced leukemia burden and increased median survival compared to either drug alone (>70 days vs 46 days (metformin) or 52 days (gilteritinib)) in cell line xenograft models (PMID: 39019012). 39019012