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

Area of Science:

• Oncology
• Pharmacology
• Hematology

Background:

• Fms-like tyrosine kinase 3 (FLT3) mutations, particularly internal tandem duplications (FLT3-ITD), are common in acute myeloid leukemia (AML) and linked to poor prognosis.
• Tyrosine kinase inhibitors (TKIs) like gilteritinib are used for FLT3-mutated AML but face challenges including drug resistance, relapse, and high cost.

Purpose of the Study:

• To investigate the synergistic effect of metformin, an anti-diabetic drug, with gilteritinib in treating FLT3-ITD AML.
• To evaluate the efficacy and safety of the metformin-gilteritinib combination in preclinical models and clinical data.

Main Methods:

• Assessed the sensitizing effect of metformin on FLT3-ITD AML cells, including TKI-resistant variants, to gilteritinib.
• Evaluated the combination's impact on leukemia progression and survival in FLT3-ITD AML mouse models.
• Analyzed the molecular mechanisms, including Polo-like kinase 1 (PLK1) and signaling pathways (FLT3/STAT5/ERK/mTOR).
• Correlated metformin use with survival outcomes in patients with FLT3-ITD AML.

Main Results:

• Metformin significantly sensitizes FLT3-ITD AML cells to gilteritinib, overcoming TKI resistance.
• The combination of metformin and low-dose gilteritinib markedly suppressed leukemia progression and prolonged survival in mouse models.
• Co-treatment cooperatively inhibited PLK1 expression and downstream signaling pathways.
• Clinical analysis indicated improved survival rates for FLT3-ITD AML patients also taking metformin.

Conclusions:

• Metformin and gilteritinib exhibit a striking synergistic effect in FLT3-ITD AML.
• The combination therapy offers a promising, cost-effective treatment strategy for FLT3-mutated AML, especially for patients with affordability concerns.