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Publication : De novo pyrimidine synthesis is a targetable vulnerability in IDH mutant glioma.

First Author  Shi DD Year  2022
Journal  Cancer Cell Volume  40
Issue  9 Pages  939-956.e16
PubMed ID  35985343 Mgi Jnum  J:328532
Mgi Id  MGI:7336628 Doi  10.1016/j.ccell.2022.07.011
Citation  Shi DD, et al. (2022) De novo pyrimidine synthesis is a targetable vulnerability in IDH mutant glioma. Cancer Cell 40(9):939-956.e16
abstractText  Mutations affecting isocitrate dehydrogenase (IDH) enzymes are prevalent in glioma, leukemia, and other cancers. Although mutant IDH inhibitors are effective against leukemia, they seem to be less active in aggressive glioma, underscoring the need for alternative treatment strategies. Through a chemical synthetic lethality screen, we discovered that IDH1-mutant glioma cells are hypersensitive to drugs targeting enzymes in the de novo pyrimidine nucleotide synthesis pathway, including dihydroorotate dehydrogenase (DHODH). We developed a genetically engineered mouse model of mutant IDH1-driven astrocytoma and used it and multiple patient-derived models to show that the brain-penetrant DHODH inhibitor BAY 2402234 displays monotherapy efficacy against IDH-mutant gliomas. Mechanistically, this reflects an obligate dependence of glioma cells on the de novo pyrimidine synthesis pathway and mutant IDH's ability to sensitize to DNA damage upon nucleotide pool imbalance. Our work outlines a tumor-selective, biomarker-guided therapeutic strategy that is poised for clinical translation.
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