ArticleCell death & disease2025
Targeting oncogenic activation of FLT3/SREBP/FASN promotes the therapeutic effect of quizartinib involving disruption of mitochondrial phospholipids.
Article in Cell death & disease, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Targeting ACSF2 overcomes Ara-C resistance in acute myeloid leukemia via the cholesterol metabolism-ERK signaling axis.Leukemia · 2026Article
- Central nervous system involvement in acute lymphoblastic leukemia: pathogenesis and targeted therapy.Leukemia · 2026Review
- Cholesterol Reprogramming in Acute Myeloid Leukemia: Integrating Tumor-Intrinsic Metabolism and Immune Crosstalk.Diseases (Basel, Switzerland) · 2026Review
- Decoding protein-phospholipid interaction networks in cancer: the role of acyl-chain remodeling.RSC chemical biology · 2026Review
- Lipid metabolism-related gene expression predicts prognostic outcomes in lung adenocarcinoma.Translational cancer research · 2026Article
- Orlistat: a comprehensive review of a lipase inhibitor from obesity management to emerging oncological applications.Frontiers in pharmacology · 2026Review
- The implications of FASN in viral infection and related diseases: a promising target in antiviral therapies.Frontiers in cellular and infection microbiology · 2026Review
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Authors and funding
10 authors.
Funding
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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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.