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

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