Targeting oncogenic activation of FLT3/SREBP/FASN promotes the therapeutic effect of quizartinib involving disruption of mitochondrial phospholipids
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 upregulatio...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2025-04-01
|
| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07661-6 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850172951385604096 |
|---|---|
| author | Feng Yin Jing Yang Hao Luo Tiantian Yu Wenhua Lu Mingyue Zhao Hongli Du Shijun Wen Peng Huang Yumin Hu |
| author_facet | Feng Yin Jing Yang Hao Luo Tiantian Yu Wenhua Lu Mingyue Zhao Hongli Du Shijun Wen Peng Huang Yumin Hu |
| author_sort | Feng Yin |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-e1a2eecd969e4d25901abdaf1890d05d |
| institution | OA Journals |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-e1a2eecd969e4d25901abdaf1890d05d2025-08-20T02:19:57ZengNature Publishing GroupCell Death and Disease2041-48892025-04-0116111410.1038/s41419-025-07661-6Targeting oncogenic activation of FLT3/SREBP/FASN promotes the therapeutic effect of quizartinib involving disruption of mitochondrial phospholipidsFeng Yin0Jing Yang1Hao Luo2Tiantian Yu3Wenhua Lu4Mingyue Zhao5Hongli Du6Shijun Wen7Peng Huang8Yumin Hu9State 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 CenterState 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 CenterState 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 CenterState 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 CenterState 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 CenterState 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 CenterSchool of Biology and Biological Engineering, South China University of TechnologyState 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 CenterState 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 CenterState 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 CenterAbstract 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.https://doi.org/10.1038/s41419-025-07661-6 |
| spellingShingle | Feng Yin Jing Yang Hao Luo Tiantian Yu Wenhua Lu Mingyue Zhao Hongli Du Shijun Wen Peng Huang Yumin Hu Targeting oncogenic activation of FLT3/SREBP/FASN promotes the therapeutic effect of quizartinib involving disruption of mitochondrial phospholipids Cell Death and Disease |
| title | Targeting oncogenic activation of FLT3/SREBP/FASN promotes the therapeutic effect of quizartinib involving disruption of mitochondrial phospholipids |
| title_full | Targeting oncogenic activation of FLT3/SREBP/FASN promotes the therapeutic effect of quizartinib involving disruption of mitochondrial phospholipids |
| title_fullStr | Targeting oncogenic activation of FLT3/SREBP/FASN promotes the therapeutic effect of quizartinib involving disruption of mitochondrial phospholipids |
| title_full_unstemmed | Targeting oncogenic activation of FLT3/SREBP/FASN promotes the therapeutic effect of quizartinib involving disruption of mitochondrial phospholipids |
| title_short | Targeting oncogenic activation of FLT3/SREBP/FASN promotes the therapeutic effect of quizartinib involving disruption of mitochondrial phospholipids |
| title_sort | targeting oncogenic activation of flt3 srebp fasn promotes the therapeutic effect of quizartinib involving disruption of mitochondrial phospholipids |
| url | https://doi.org/10.1038/s41419-025-07661-6 |
| work_keys_str_mv | AT fengyin targetingoncogenicactivationofflt3srebpfasnpromotesthetherapeuticeffectofquizartinibinvolvingdisruptionofmitochondrialphospholipids AT jingyang targetingoncogenicactivationofflt3srebpfasnpromotesthetherapeuticeffectofquizartinibinvolvingdisruptionofmitochondrialphospholipids AT haoluo targetingoncogenicactivationofflt3srebpfasnpromotesthetherapeuticeffectofquizartinibinvolvingdisruptionofmitochondrialphospholipids AT tiantianyu targetingoncogenicactivationofflt3srebpfasnpromotesthetherapeuticeffectofquizartinibinvolvingdisruptionofmitochondrialphospholipids AT wenhualu targetingoncogenicactivationofflt3srebpfasnpromotesthetherapeuticeffectofquizartinibinvolvingdisruptionofmitochondrialphospholipids AT mingyuezhao targetingoncogenicactivationofflt3srebpfasnpromotesthetherapeuticeffectofquizartinibinvolvingdisruptionofmitochondrialphospholipids AT honglidu targetingoncogenicactivationofflt3srebpfasnpromotesthetherapeuticeffectofquizartinibinvolvingdisruptionofmitochondrialphospholipids AT shijunwen targetingoncogenicactivationofflt3srebpfasnpromotesthetherapeuticeffectofquizartinibinvolvingdisruptionofmitochondrialphospholipids AT penghuang targetingoncogenicactivationofflt3srebpfasnpromotesthetherapeuticeffectofquizartinibinvolvingdisruptionofmitochondrialphospholipids AT yuminhu targetingoncogenicactivationofflt3srebpfasnpromotesthetherapeuticeffectofquizartinibinvolvingdisruptionofmitochondrialphospholipids |