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IDH-mutant enzymes synthesize (\n                  <jats:italic>R<\/jats:italic>\n                  )-2-hydroxyglutarate (R2HG), which broadly inhibits 2-oxoglutarate-dependent enzymes. We performed forward genetic screens targeting all 2-oxoglutarate-dependent enzymes and discovered that KDM6 histone demethylases play a vital role in protecting cells from replication stress. Genetic or R2HG-mediated repression of KDM6 catalytic activity sensitized glioma cells to disparate replication stress-inducing drugs, including Ataxia-telangiectasia and Rad3-related (ATR) and dihydroorotate dehydrogenase (DHODH) inhibitors. This liability is generalizable because KDM6A loss-of-function mutations commonly observed in urothelial carcinomas sensitized bladder cancer cells to DHODH inhibition, thereby phenocopying IDH mutations in glioma. To exploit these oncogene-induced replication stress vulnerabilities, we developed an effective, on-target, and well-tolerated DHODH inhibitor, GLIO-1, that is poised for clinical translation. Collectively, we reveal KDM6 activity as a fundamental determinant of replication stress sensitivity and nominate pan-cancer, mechanism-based biomarkers of ATR and DHODH inhibitor efficacy.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>STATEMENT OF SIGNIFICANCE<\/jats:title>\n                  <jats:p>We discovered that the KDM6 enzymes are the mechanistic targets of R2HG that mediate mutant IDH-induced replication stress hypersensitivity. We report a promising new DHODH inhibitor, GLIO-1, and nominate KDM6 and IDH mutations as predictive biomarkers for the antitumor effects of GLIO-1 and other replication stress inducers.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.04.14.715350","type":"posted-content","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T19:30:27Z","timestamp":1776454227000},"source":"Crossref","is-referenced-by-count":1,"title":["KDM6 Enzymes are the Mechanistic Targets of Mutant IDH that Dictate Replication Stress Sensitivity"],"prefix":"10.64898","author":[{"given":"Alexander C.-Y.","family":"Tsai","sequence":"first","affiliation":[{"name":"Department of Radiation Oncology, Mass General Brigham, Harvard Medical School, Boston, MA, USA"},{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathew D.","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinesh T.","family":"Puliyappadamba","sequence":"additional","affiliation":[{"name":"Children\u2019s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorothy M.","family":"Junginger","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Mass General Brigham, Harvard Medical School, Boston, MA, USA"},{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria G.","family":"Donovan","sequence":"additional","affiliation":[{"name":"Department of Animal Resources, Dana-Farber Cancer Institute, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleanor G.","family":"Kaplan","sequence":"additional","affiliation":[{"name":"Broad Institute of MIT and Harvard, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura M.","family":"Drepanos","sequence":"additional","affiliation":[{"name":"Broad Institute of MIT and Harvard, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroaki","family":"Wakimoto","sequence":"additional","affiliation":[{"name":"Translational Neuro-Oncology Laboratory, Department of Neurosurgery, Mass General Brigham, Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel P.","family":"Cahill","sequence":"additional","affiliation":[{"name":"Translational Neuro-Oncology Laboratory, Department of Neurosurgery, Mass General Brigham, Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie A.","family":"Losman","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kent W.","family":"Mouw","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kalil G.","family":"Abdullah","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA"},{"name":"Hillman Comprehensive Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John G.","family":"Doench","sequence":"additional","affiliation":[{"name":"Broad Institute of MIT and Harvard, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duane","family":"Nash","sequence":"additional","affiliation":[{"name":"Gliomic Therapeutics, San Diego, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Vitt","sequence":"additional","affiliation":[{"name":"Immunic AG, Gr\u00e4felfing, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Gege","sequence":"additional","affiliation":[{"name":"Immunic AG, Gr\u00e4felfing, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hella","family":"Kohlhof","sequence":"additional","affiliation":[{"name":"Immunic AG, Gr\u00e4felfing, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel K.","family":"McBrayer","sequence":"additional","affiliation":[{"name":"Children\u2019s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA"},{"name":"Harold C. 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