1. De novo pyrimidine synthesis is a targetable vulnerability in IDH mutant glioma.
- Author
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Shi DD, Savani MR, Levitt MM, Wang AC, Endress JE, Bird CE, Buehler J, Stopka SA, Regan MS, Lin YF, 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, Nguyen QD, Signoretti S, Gradl S, Sutter A, Jeffers M, Janzer A, Lehrman MA, Zacharias LG, Mathews TP, Losman JA, Richardson TE, Cahill DP, DeBerardinis RJ, Ligon KL, Xu L, Ly P, Agar NYR, Abdullah KG, Harris IS, Kaelin WG Jr, and McBrayer SK
- Subjects
- Animals, Enzyme Inhibitors therapeutic use, Isocitrate Dehydrogenase genetics, Isocitrate Dehydrogenase metabolism, Mice, Mutation, Pyrimidines pharmacology, Pyrimidines therapeutic use, Salicylanilides, Triazoles, Brain Neoplasms drug therapy, Brain Neoplasms genetics, Glioma drug therapy, Glioma genetics, Leukemia
- 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., Competing Interests: Declaration of interests R.J.D., W.G.K., and S.K.M. have served as paid advisors to Agios Pharmaceuticals. W.G.K. receives compensation for roles as an Eli Lilly and LifeMine Therapeutics Board Director, a founder of Tango Therapeutics and Cedilla Therapeutics, and a scientific advisor for Fibrogen, IconOVir Bio, Circle Pharma, Nextext Invest, and Casdin Capital. K.L.L. receives research support from Eli Lilly and Company via the DFCI. S.K.M. and W.G.K. received research funding from Bayer Pharmaceuticals. Bayer had no influence over the design, execution, or interpretation of studies. N.Y.R.A. is key opinion leader for Bruker Daltonics, scientific advisor to Invicro, and receives support from Thermo Finnegan and EMD Serono. S.G., A.S., M.S., A.J., and L.E. are employees at Bayer. S.G., A.S., and A.J. hold stock in Bayer. D.P.C. has consulted for Lilly, GlaxoSmithKline, and Boston Pharmaceuticals and serves on the advisory board of Pyramid Biosciences, which includes an equity interest. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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