Title | De novo pyrimidine synthesis is a targetable vulnerability in IDH mutant glioma. |
Publication Type | Journal Article |
Year of Publication | 2022 |
Authors | Shi DD, Savani MR, Levitt MM, Wang AC, Endress JE, Bird CE, Buehler J, Stopka SA, Regan MS, Lin Y-F, Puliyappadamba VT, Gao W, Khanal J, Evans L, Lee JH, Guo L, Xiao Y, Xu M, Huang B, Jennings RB, Bonal DM, Martin-Sandoval MS, Dang T, Gattie LC, Cameron AB, Lee S, Asara JM, Kornblum HI, Mak TW, Looper RE, De Nguyen Q-, Signoretti S, Gradl S, Sutter A, Jeffers M, Janzer A, Lehrman MA, Zacharias LG, Mathews TP, Losman J-A, Richardson TE, Cahill DP, DeBerardinis RJ, Ligon KL, Xu L, Ly P, Agar NYR, Abdullah KG, Harris IS, Kaelin WG, McBrayer SK |
Journal | Cancer Cell |
Volume | 40 |
Issue | 9 |
Pagination | 939-956.e16 |
Date Published | 2022 Sep 12 |
ISSN | 1878-3686 |
Keywords | Animals, Brain Neoplasms, Enzyme Inhibitors, Glioma, Isocitrate Dehydrogenase, Leukemia, Mice, Mutation, Pyrimidines, Salicylanilides, Triazoles |
Abstract | 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. |
DOI | 10.1016/j.ccell.2022.07.011 |
Alternate Journal | Cancer Cell |
PubMed ID | 35985343 |
PubMed Central ID | PMC9515386 |
Grant List | U19 CA264504 / CA / NCI NIH HHS / United States F30 CA183474 / CA / NCI NIH HHS / United States K22 CA237752 / CA / NCI NIH HHS / United States F30 CA271634 / CA / NCI NIH HHS / United States R35 CA220449 / CA / NCI NIH HHS / United States R01 CA188652 / CA / NCI NIH HHS / United States P50 CA211015 / CA / NCI NIH HHS / United States R01 CA258586 / CA / NCI NIH HHS / United States P30 CA006516 / CA / NCI NIH HHS / United States P50 CA165962 / CA / NCI NIH HHS / United States U54 CA210180 / CA / NCI NIH HHS / United States P01 CA120964 / CA / NCI NIH HHS / United States P41 EB028741 / EB / NIBIB NIH HHS / United States T32 GM007753 / GM / NIGMS NIH HHS / United States R35 CA210068 / CA / NCI NIH HHS / United States |