Metformin synergizes with gilteritinib in treating FLT3-mutated leukemia via targeting PLK1 signaling.
Cell Rep Med
; 5(7): 101645, 2024 Jul 16.
Article
en En
| MEDLINE
| ID: mdl-39019012
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Pirazinas
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Leucemia Mieloide Aguda
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Transducción de Señal
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Proteínas Proto-Oncogénicas
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Proteínas Serina-Treonina Quinasas
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Proteínas de Ciclo Celular
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Sinergismo Farmacológico
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Tirosina Quinasa 3 Similar a fms
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Quinasa Tipo Polo 1
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Compuestos de Anilina
Idioma:
En
Revista:
Cell Rep Med
Año:
2024
Tipo del documento:
Article