2. Academic Validation
  3. Metformin synergizes with gilteritinib in treating FLT3-mutated leukemia via targeting PLK1 signaling

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

  • Cell Rep Med. 2024 Jul 16;5(7):101645. doi: 10.1016/j.xcrm.2024.101645.
Meiling Chen 1,  Chao Shen 2,  Yi Chen 3,  Zhenhua Chen 4,  Keren Zhou 5,  Yuanzhong Chen 3,  Wei Li 4,  Chengwu Zeng 6,  Ying Qing 4,  Dong Wu 7,  Caiming Xu 8,  Tingting Tang 4,  Yuan Che 4,  Xi Qin 4,  Zhaoxu Xu 4,  Kitty Wang 4,  Keith Leung 4,  Lillian Sau 4,  Xiaolan Deng 9,  Jianda Hu 10,  Yong Wu 11,  Jianjun Chen 12
Affiliations

Affiliations

  • 1 Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, China; Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; Center for RNA Biology and Therapeutics, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
  • 2 Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; Center for RNA Biology and Therapeutics, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. Electronic address: chashen@coh.org.
  • 3 Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, China.
  • 4 Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; Center for RNA Biology and Therapeutics, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
  • 5 Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA.
  • 6 Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; Department of Hematology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510700, China.
  • 7 Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; Center for RNA Biology and Therapeutics, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA; Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China.
  • 8 Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Biomedical Research Center, Monrovia, CA 91016, USA.
  • 9 Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; Center for RNA Biology and Therapeutics, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. Electronic address: xideng@coh.org.
  • 10 Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, China; Department of Hematology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian 362000, China. Electronic address: drjiandahu@163.com.
  • 11 Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, China. Electronic address: wuyong9195@126.com.
  • 12 Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; Center for RNA Biology and Therapeutics, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. Electronic address: jianchen@coh.org.
PMID: 39019012 DOI: 10.1016/j.xcrm.2024.101645
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.

Keywords

AML; FLT3-ITD; FLT3-mutated; MAPK/mTOR; PLK1; TKI-resistant; combinational therapy; gilteritinib; metformin; synergy.

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