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
  • 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
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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