Targeting oncogenic activation of FLT3/SREBP/FASN promotes the therapeutic effect of quizartinib involving disruption of mitochondrial phospholipids

  • Cell Death Dis. 2025 Apr 22;16(1):327. doi: 10.1038/s41419-025-07661-6.
Feng Yin  1 ,  Jing Yang  1 ,  Hao Luo  1 ,  Tiantian Yu  1  2 ,  Wenhua Lu  1 ,  Mingyue Zhao  1 ,  Hongli Du  3 ,  Shijun Wen  1 ,  Peng Huang  1  2 ,  Yumin Hu  4  5
Affiliations
  • 1. State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Cancer Metabolism and Intervention Research Center, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, China.
  • 2. Metabolomics Research Center, Sun Yat-sen University Zhongshan School of Medicine, Guangzhou, 510080, China.
  • 3. School of Biology and Biological Engineering, South China University of Technology, Guangzhou, 510006, Guangdong, China.
  • 4. State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Cancer Metabolism and Intervention Research Center, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, China. [email protected].
  • 5. Metabolomics Research Center, Sun Yat-sen University Zhongshan School of Medicine, Guangzhou, 510080, China. [email protected].
PMID: 40263296 DOI: 10.1038/s41419-025-07661-6
Abstract

FMS-like tyrosine kinase 3-internal tandem duplication (FLT3/ITD) is a common driver mutation that presents with a high leukemic burden and its impact on metabolic homeostasis remains to be further investigated. Here, we revealed that the oncogenic activation of FLT3/ITD induced upregulation of target genes of sterol regulatory element-binding proteins (SREBPs) in vivo and in acute myeloid leukemia patients. Quizartinib is a second-generation FLT3 Inhibitor that selectively inhibits the activating FLT3 mutations. We demonstrated the critical role of SREBP1 degradation in conferring the response of FLT3/ITD cells to quizartinib. Mechanistically, quizartinib facilitated degradation of the precursor form of SREBP1 via the FLT3/Akt/GSK3 axis and reduced protein levels of its target gene fatty acid synthase (FASN). Lipidomics analysis by Liquid Chromatography Mass Spectrometry (LC-MS) demonstrated that inhibition of FLT3 altered global levels of Phospholipids including reduction of cardiolipin, leading to subsequent loss of mitochondrial membrane potential. Pharmacological inhibition of SREBP1 or FASN sensitized FLT3/ITD leukemia cells to quizartinib. Quizartinib combined with SREBP inhibitor fatostatin or FASN inhibitor orlistat provided substantial therapeutic benefit over monotherapies in the murine FLT3/ITD leukemia model. Our results indicated the mechanistic link between FLT3/ITD and SREBP degradation and suggested the combination therapy via targeting FLT3/SREBP/FASN axis.

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