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

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

doi:10.1016/j.xcrm.2024.101645

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.

Authors

Meiling Chen¹, Chao Shen², Yi Chen³, Zhenhua Chen⁴, Keren Zhou⁵, Yuanzhong Chen³, Wei Li⁴, Chengwu Zeng⁶, Ying Qing⁴, Dong Wu⁷, Caiming Xu⁸, Tingting Tang⁴, Yuan Che⁴, Xi Qin⁴, Zhaoxu Xu⁴, Kitty Wang⁴, Keith Leung⁴, Lillian Sau⁴, Xiaolan Deng⁹, Jianda Hu¹⁰, Yong Wu¹¹, Jianjun Chen¹²

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.

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.

MeSH terms

Aniline Compounds* / pharmacology
Aniline Compounds* / therapeutic use
Animals
Cell Cycle Proteins* / genetics
Cell Cycle Proteins* / metabolism
Cell Line, Tumor
Drug Resistance, Neoplasm / drug effects
Drug Resistance, Neoplasm / genetics
Drug Synergism*
Female
Humans
Leukemia, Myeloid, Acute* / drug therapy
Leukemia, Myeloid, Acute* / genetics
Leukemia, Myeloid, Acute* / pathology
Male
Metformin* / pharmacology
Metformin* / therapeutic use
Mice
Mutation* / genetics
Polo-Like Kinase 1*
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use
Protein Serine-Threonine Kinases* / antagonists & inhibitors
Protein Serine-Threonine Kinases* / genetics
Protein Serine-Threonine Kinases* / metabolism
Proto-Oncogene Proteins* / antagonists & inhibitors
Proto-Oncogene Proteins* / genetics
Proto-Oncogene Proteins* / metabolism
Pyrazines* / pharmacology
Pyrazines* / therapeutic use
STAT5 Transcription Factor / genetics
STAT5 Transcription Factor / metabolism
Signal Transduction* / drug effects
TOR Serine-Threonine Kinases / metabolism
Thiophenes / pharmacology
Thiophenes / therapeutic use
Xenograft Model Antitumor Assays
fms-Like Tyrosine Kinase 3* / antagonists & inhibitors
fms-Like Tyrosine Kinase 3* / genetics
fms-Like Tyrosine Kinase 3* / metabolism

Substances

Metformin
fms-Like Tyrosine Kinase 3
gilteritinib
Proto-Oncogene Proteins
Polo-Like Kinase 1
Cell Cycle Proteins
Protein Serine-Threonine Kinases
Pyrazines
Aniline Compounds
FLT3 protein, human
Thiophenes
Protein Kinase Inhibitors
STAT5 Transcription Factor
TOR Serine-Threonine Kinases

Abstract

MeSH terms

Substances

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