The internal tandem duplication of the FMS-like tyrosine kinase 3 (FLT3-ITD) is one of the most frequent genetic alterations in acute myeloid leukemia (AML). Limited and transient clinical benefit of FLT3 kinase inhibitors (FLT3i) emphasizes the need for alternative therapeutic options for this subset of myeloid malignancies. Herein, we showed that FLT3-ITD mutant (FLT3-ITD+) AML cells were susceptible toward inhibitors of DHODH, a rate-limiting enzyme of de novo pyrimidine biosynthesis. Genetic and pharmacological blockade of DHODH triggered downregulation of FLT3-ITD protein, subsequently suppressed activation of downstream ERK and STAT5, and promoted cell death of FLT3-ITD+ AML cells. Mechanistically, DHODH blockade triggered autophagy-mediated FLT3-ITD degradation via inactivating mTOR, a potent autophagy repressor. Notably, blockade of DHODH synergized with an FDA-approved FLT3i quizartinib in significantly impairing the growth of FLT3-ITD+ AML cells and improving tumor-bearing mice survival. We further demonstrated that DHODH blockade exhibited profound anti-proliferation effect on quizartinib-resistant cells in vitro and in vivo. In summary, this study demonstrates that the induction of degradation of FLT3-ITD protein by DHODH blockade may offer a promising therapeutic strategy for AML patients harboring FLT3-ITD mutation.
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This project was supported by the National Natural Science Foundation of China (81973362, 82173857), Shanghai Committee of Science and Technology (22S11900900), Guangdong Provincial Medical Science and Technology Research Fund (B2021077) and Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism. We thank the Ministry of Education and the Research Center of Analysis and Test of East China University of Science and Technology.
The authors declare no competing interests.
All animal studies and protocols were approved by the Animal Experiments Committee of East China University of Science and Technology (ECUST-2021-03007).
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Ma, H., Cui, J., Liu, Z. et al. Blockade of de novo pyrimidine biosynthesis triggers autophagic degradation of oncoprotein FLT3-ITD in acute myeloid leukemia. Oncogene 42, 3331–3343 (2023). https://doi.org/10.1038/s41388-023-02848-7