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Disabling Uncompetitive Inhibition of Oncogenic IDH Mutations Drives Acquired Resistance
Mutations in IDH genes occur frequently in acute myeloid leukemia (AML) and other human cancers to generate the oncometabolite R-2HG. 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 und...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for Cancer Research
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9827114/ https://www.ncbi.nlm.nih.gov/pubmed/36222845 http://dx.doi.org/10.1158/2159-8290.CD-21-1661 |
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author | Lyu, Junhua Liu, Yuxuan Gong, Lihu Chen, Mingyi Madanat, Yazan F. Zhang, Yuannyu Cai, Feng Gu, Zhimin Cao, Hui Kaphle, Pranita Kim, Yoon Jung Kalkan, Fatma N. Stephens, Helen Dickerson, Kathryn E. Ni, Min Chen, Weina Patel, Prapti Mims, Alice S. Borate, Uma Burd, Amy Cai, Sheng F. Yin, C. Cameron You, M. James Chung, Stephen S. Collins, Robert H. DeBerardinis, Ralph J. Liu, Xin Xu, Jian |
author_facet | Lyu, Junhua Liu, Yuxuan Gong, Lihu Chen, Mingyi Madanat, Yazan F. Zhang, Yuannyu Cai, Feng Gu, Zhimin Cao, Hui Kaphle, Pranita Kim, Yoon Jung Kalkan, Fatma N. Stephens, Helen Dickerson, Kathryn E. Ni, Min Chen, Weina Patel, Prapti Mims, Alice S. Borate, Uma Burd, Amy Cai, Sheng F. Yin, C. Cameron You, M. James Chung, Stephen S. Collins, Robert H. DeBerardinis, Ralph J. Liu, Xin Xu, Jian |
author_sort | Lyu, Junhua |
collection | PubMed |
description | Mutations in IDH genes occur frequently in acute myeloid leukemia (AML) and other human cancers to generate the oncometabolite R-2HG. 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–inhibitor 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. SIGNIFICANCE: 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. This article is highlighted in the In This Issue feature, p. 1 |
format | Online Article Text |
id | pubmed-9827114 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Association for Cancer Research |
record_format | MEDLINE/PubMed |
spelling | pubmed-98271142023-01-10 Disabling Uncompetitive Inhibition of Oncogenic IDH Mutations Drives Acquired Resistance Lyu, Junhua Liu, Yuxuan Gong, Lihu Chen, Mingyi Madanat, Yazan F. Zhang, Yuannyu Cai, Feng Gu, Zhimin Cao, Hui Kaphle, Pranita Kim, Yoon Jung Kalkan, Fatma N. Stephens, Helen Dickerson, Kathryn E. Ni, Min Chen, Weina Patel, Prapti Mims, Alice S. Borate, Uma Burd, Amy Cai, Sheng F. Yin, C. Cameron You, M. James Chung, Stephen S. Collins, Robert H. DeBerardinis, Ralph J. Liu, Xin Xu, Jian Cancer Discov Research Articles Mutations in IDH genes occur frequently in acute myeloid leukemia (AML) and other human cancers to generate the oncometabolite R-2HG. 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–inhibitor 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. SIGNIFICANCE: 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. This article is highlighted in the In This Issue feature, p. 1 American Association for Cancer Research 2023-01-09 2022-10-12 /pmc/articles/PMC9827114/ /pubmed/36222845 http://dx.doi.org/10.1158/2159-8290.CD-21-1661 Text en ©2022 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license. |
spellingShingle | Research Articles Lyu, Junhua Liu, Yuxuan Gong, Lihu Chen, Mingyi Madanat, Yazan F. Zhang, Yuannyu Cai, Feng Gu, Zhimin Cao, Hui Kaphle, Pranita Kim, Yoon Jung Kalkan, Fatma N. Stephens, Helen Dickerson, Kathryn E. Ni, Min Chen, Weina Patel, Prapti Mims, Alice S. Borate, Uma Burd, Amy Cai, Sheng F. Yin, C. Cameron You, M. James Chung, Stephen S. Collins, Robert H. DeBerardinis, Ralph J. Liu, Xin Xu, Jian Disabling Uncompetitive Inhibition of Oncogenic IDH Mutations Drives Acquired Resistance |
title | Disabling Uncompetitive Inhibition of Oncogenic IDH Mutations Drives Acquired Resistance |
title_full | Disabling Uncompetitive Inhibition of Oncogenic IDH Mutations Drives Acquired Resistance |
title_fullStr | Disabling Uncompetitive Inhibition of Oncogenic IDH Mutations Drives Acquired Resistance |
title_full_unstemmed | Disabling Uncompetitive Inhibition of Oncogenic IDH Mutations Drives Acquired Resistance |
title_short | Disabling Uncompetitive Inhibition of Oncogenic IDH Mutations Drives Acquired Resistance |
title_sort | disabling uncompetitive inhibition of oncogenic idh mutations drives acquired resistance |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9827114/ https://www.ncbi.nlm.nih.gov/pubmed/36222845 http://dx.doi.org/10.1158/2159-8290.CD-21-1661 |
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