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

IF 11.7 1区医学 Q1 CELL BIOLOGY Cell Reports Medicine Pub Date : 2024-07-16 DOI:10.1016/j.xcrm.2024.101645

Meiling Chen, Chao Shen, Yi Chen, Zhenhua Chen, Keren Zhou, Yuanzhong Chen, Wei Li, Chengwu Zeng, Ying Qing, Dong Wu, Caiming Xu, Tingting Tang, Yuan Che, Xi Qin, Zhaoxu Xu, Kitty Wang, Keith Leung, Lillian Sau, Xiaolan Deng, Jianda Hu, Yong Wu, Jianjun Chen

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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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二甲双胍与吉特替尼通过靶向 PLK1 信号协同治疗 FLT3 基因突变的白血病。

30%以上的急性髓性白血病（AML）病例存在FMS样酪氨酸激酶3（FLT3）突变，以FLT3-内部串联重复（FLT3-ITD）为主，这与AML患者的不良预后有关。虽然酪氨酸激酶抑制剂（TKIs，如吉利替尼）很有效，但它们也面临着耐药性、复发和高成本等挑战。在此，我们报告了二甲双胍（一种廉价、安全且广泛使用的抗糖尿病药物）与吉尔替尼在治疗 FLT3-ITD AML 方面表现出惊人的协同效应。二甲双胍能使 FLT3-ITD AML 细胞（包括 TKI 耐药细胞）对吉尔替尼明显敏感。在FLT3-ITD急性髓细胞白血病小鼠模型中，二甲双胍加吉特替尼（小剂量）可明显抑制白血病的进展并延长生存期。从机理上讲，联合治疗可协同抑制多聚样激酶1（PLK1）的表达和FLT3/STAT5/ERK/mTOR的磷酸化。临床分析还显示，FLT3-ITD AML 患者服用二甲双胍后生存率有所提高。因此，二甲双胍/吉特替尼联合疗法是治疗FLT3突变急性髓细胞性白血病患者（尤其是低收入/负担能力差的患者）的一种前景广阔且经济有效的治疗方法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Reports Medicine Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)

CiteScore

15.00

自引率

1.40%

发文量

231

审稿时长

40 days

期刊介绍： Cell Reports Medicine is an esteemed open-access journal by Cell Press that publishes groundbreaking research in translational and clinical biomedical sciences, influencing human health and medicine. Our journal ensures wide visibility and accessibility, reaching scientists and clinicians across various medical disciplines. We publish original research that spans from intriguing human biology concepts to all aspects of clinical work. We encourage submissions that introduce innovative ideas, forging new paths in clinical research and practice. We also welcome studies that provide vital information, enhancing our understanding of current standards of care in diagnosis, treatment, and prognosis. This encompasses translational studies, clinical trials (including long-term follow-ups), genomics, biomarker discovery, and technological advancements that contribute to diagnostics, treatment, and healthcare. Additionally, studies based on vertebrate model organisms are within the scope of the journal, as long as they directly relate to human health and disease.