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Allosteric inhibition of mutant IDH suppresses R-2HG production in a subset of patients with AML; however, acquired resistance emerges as a new challenge, and the underlying mechanisms remain incompletely understood. Here we establish isogenic leukemia cells containing common IDH oncogenic mutations by CRISPR base editing. By mutational scanning of IDH single amino acid variants in base-edited cells, we describe a repertoire of IDH second-site mutations responsible for therapy resistance through disabling uncompetitive enzyme inhibition. Recurrent mutations at NADPH binding sites within IDH heterodimers act in cis or trans to prevent the formation of stable enzyme\u2013inhibitor complexes, restore R-2HG production in the presence of inhibitors, and drive therapy resistance in IDH-mutant AML cells and patients. We therefore uncover a new class of pathogenic mutations and mechanisms for acquired resistance to targeted cancer therapies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>Comprehensive scanning of IDH single amino acid variants in base-edited leukemia cells uncovers recurrent mutations conferring resistance to IDH inhibition through disabling NADPH-dependent uncompetitive inhibition. Together with targeted sequencing, structural, and functional studies, we identify a new class of pathogenic mutations and mechanisms for acquired resistance to IDH-targeting cancer therapies.<\/jats:p>\n                    <jats:p>This article is highlighted in the In This Issue feature, p. 1<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-21-1661","type":"journal-article","created":{"date-parts":[[2022,10,12]],"date-time":"2022-10-12T11:02:55Z","timestamp":1665572575000},"page":"170-193","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Disabling Uncompetitive Inhibition of Oncogenic IDH Mutations Drives Acquired Resistance"],"prefix":"10.1158","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9617-0343","authenticated-orcid":false,"given":"Junhua","family":"Lyu","sequence":"first","affiliation":[{"name":"1Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas."},{"name":"2Department of Pediatrics, Harold C. Simmons Comprehensive Cancer Center, and Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7060-6954","authenticated-orcid":false,"given":"Yuxuan","family":"Liu","sequence":"additional","affiliation":[{"name":"1Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas."},{"name":"2Department of Pediatrics, Harold C. Simmons Comprehensive Cancer Center, and Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5482-2120","authenticated-orcid":false,"given":"Lihu","family":"Gong","sequence":"additional","affiliation":[{"name":"3Cecil H. and Ida Green Center for Reproductive Biology Sciences, Department of Obstetrics and Gynecology, and Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6754-0480","authenticated-orcid":false,"given":"Mingyi","family":"Chen","sequence":"additional","affiliation":[{"name":"4Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9573-2690","authenticated-orcid":false,"given":"Yazan F.","family":"Madanat","sequence":"additional","affiliation":[{"name":"5Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7016-7557","authenticated-orcid":false,"given":"Yuannyu","family":"Zhang","sequence":"additional","affiliation":[{"name":"1Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas."},{"name":"2Department of Pediatrics, Harold C. Simmons Comprehensive Cancer Center, and Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5192-9520","authenticated-orcid":false,"given":"Feng","family":"Cai","sequence":"additional","affiliation":[{"name":"1Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8150-2560","authenticated-orcid":false,"given":"Zhimin","family":"Gu","sequence":"additional","affiliation":[{"name":"1Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas."},{"name":"2Department of Pediatrics, Harold C. Simmons Comprehensive Cancer Center, and Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3471-4434","authenticated-orcid":false,"given":"Hui","family":"Cao","sequence":"additional","affiliation":[{"name":"1Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas."},{"name":"2Department of Pediatrics, Harold C. Simmons Comprehensive Cancer Center, and Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2984-666X","authenticated-orcid":false,"given":"Pranita","family":"Kaphle","sequence":"additional","affiliation":[{"name":"1Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas."},{"name":"2Department of Pediatrics, Harold C. Simmons Comprehensive Cancer Center, and Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2942-294X","authenticated-orcid":false,"given":"Yoon Jung","family":"Kim","sequence":"additional","affiliation":[{"name":"1Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas."},{"name":"2Department of Pediatrics, Harold C. Simmons Comprehensive Cancer Center, and Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1053-1193","authenticated-orcid":false,"given":"Fatma N.","family":"Kalkan","sequence":"additional","affiliation":[{"name":"5Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5741-6662","authenticated-orcid":false,"given":"Helen","family":"Stephens","sequence":"additional","affiliation":[{"name":"5Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1220-2243","authenticated-orcid":false,"given":"Kathryn E.","family":"Dickerson","sequence":"additional","affiliation":[{"name":"1Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas."},{"name":"2Department of Pediatrics, Harold C. Simmons Comprehensive Cancer Center, and Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4587-1622","authenticated-orcid":false,"given":"Min","family":"Ni","sequence":"additional","affiliation":[{"name":"1Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5638-4371","authenticated-orcid":false,"given":"Weina","family":"Chen","sequence":"additional","affiliation":[{"name":"4Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8865-4492","authenticated-orcid":false,"given":"Prapti","family":"Patel","sequence":"additional","affiliation":[{"name":"5Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8971-2199","authenticated-orcid":false,"given":"Alice S.","family":"Mims","sequence":"additional","affiliation":[{"name":"6Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4958-4962","authenticated-orcid":false,"given":"Uma","family":"Borate","sequence":"additional","affiliation":[{"name":"7Division of Hematology and Medical Oncology, Department of Medicine, Oregon Health and Science University, Portland, Oregon."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9625-2813","authenticated-orcid":false,"given":"Amy","family":"Burd","sequence":"additional","affiliation":[{"name":"8The Leukemia & Lymphoma Society, Rye Brook, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2708-887X","authenticated-orcid":false,"given":"Sheng F.","family":"Cai","sequence":"additional","affiliation":[{"name":"9Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6630-4128","authenticated-orcid":false,"given":"C. Cameron","family":"Yin","sequence":"additional","affiliation":[{"name":"10Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9111-8068","authenticated-orcid":false,"given":"M. James","family":"You","sequence":"additional","affiliation":[{"name":"10Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1433-7419","authenticated-orcid":false,"given":"Stephen S.","family":"Chung","sequence":"additional","affiliation":[{"name":"5Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0313-2394","authenticated-orcid":false,"given":"Robert H.","family":"Collins","sequence":"additional","affiliation":[{"name":"5Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2705-7432","authenticated-orcid":false,"given":"Ralph J.","family":"DeBerardinis","sequence":"additional","affiliation":[{"name":"1Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas."},{"name":"11Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5646-423X","authenticated-orcid":false,"given":"Xin","family":"Liu","sequence":"additional","affiliation":[{"name":"3Cecil H. and Ida Green Center for Reproductive Biology Sciences, Department of Obstetrics and Gynecology, and Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1988-7337","authenticated-orcid":false,"given":"Jian","family":"Xu","sequence":"additional","affiliation":[{"name":"1Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas."},{"name":"2Department of Pediatrics, Harold C. Simmons Comprehensive Cancer Center, and Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1086","published-online":{"date-parts":[[2022,10,12]]},"reference":[{"key":"2025121006584713200_bib1","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.1126\/science.1164382","article-title":"An integrated genomic analysis of human glioblastoma multiforme","volume":"321","author":"Parsons","year":"2008","journal-title":"Science"},{"key":"2025121006584713200_bib2","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1056\/NEJMoa0808710","article-title":"IDH1 and IDH2 mutations in gliomas","volume":"360","author":"Yan","year":"2009","journal-title":"N Engl J Med"},{"key":"2025121006584713200_bib3","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1056\/NEJMoa0903840","article-title":"Recurring mutations found by sequencing an acute myeloid 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