Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for Cancer Research 2023
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
_version_ 1784867005305716736
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
work_keys_str_mv AT lyujunhua disablinguncompetitiveinhibitionofoncogenicidhmutationsdrivesacquiredresistance
AT liuyuxuan disablinguncompetitiveinhibitionofoncogenicidhmutationsdrivesacquiredresistance
AT gonglihu disablinguncompetitiveinhibitionofoncogenicidhmutationsdrivesacquiredresistance
AT chenmingyi disablinguncompetitiveinhibitionofoncogenicidhmutationsdrivesacquiredresistance
AT madanatyazanf disablinguncompetitiveinhibitionofoncogenicidhmutationsdrivesacquiredresistance
AT zhangyuannyu disablinguncompetitiveinhibitionofoncogenicidhmutationsdrivesacquiredresistance
AT caifeng disablinguncompetitiveinhibitionofoncogenicidhmutationsdrivesacquiredresistance
AT guzhimin disablinguncompetitiveinhibitionofoncogenicidhmutationsdrivesacquiredresistance
AT caohui disablinguncompetitiveinhibitionofoncogenicidhmutationsdrivesacquiredresistance
AT kaphlepranita disablinguncompetitiveinhibitionofoncogenicidhmutationsdrivesacquiredresistance
AT kimyoonjung disablinguncompetitiveinhibitionofoncogenicidhmutationsdrivesacquiredresistance
AT kalkanfatman disablinguncompetitiveinhibitionofoncogenicidhmutationsdrivesacquiredresistance
AT stephenshelen disablinguncompetitiveinhibitionofoncogenicidhmutationsdrivesacquiredresistance
AT dickersonkathryne disablinguncompetitiveinhibitionofoncogenicidhmutationsdrivesacquiredresistance
AT nimin disablinguncompetitiveinhibitionofoncogenicidhmutationsdrivesacquiredresistance
AT chenweina disablinguncompetitiveinhibitionofoncogenicidhmutationsdrivesacquiredresistance
AT patelprapti disablinguncompetitiveinhibitionofoncogenicidhmutationsdrivesacquiredresistance
AT mimsalices disablinguncompetitiveinhibitionofoncogenicidhmutationsdrivesacquiredresistance
AT borateuma disablinguncompetitiveinhibitionofoncogenicidhmutationsdrivesacquiredresistance
AT burdamy disablinguncompetitiveinhibitionofoncogenicidhmutationsdrivesacquiredresistance
AT caishengf disablinguncompetitiveinhibitionofoncogenicidhmutationsdrivesacquiredresistance
AT yinccameron disablinguncompetitiveinhibitionofoncogenicidhmutationsdrivesacquiredresistance
AT youmjames disablinguncompetitiveinhibitionofoncogenicidhmutationsdrivesacquiredresistance
AT chungstephens disablinguncompetitiveinhibitionofoncogenicidhmutationsdrivesacquiredresistance
AT collinsroberth disablinguncompetitiveinhibitionofoncogenicidhmutationsdrivesacquiredresistance
AT deberardinisralphj disablinguncompetitiveinhibitionofoncogenicidhmutationsdrivesacquiredresistance
AT liuxin disablinguncompetitiveinhibitionofoncogenicidhmutationsdrivesacquiredresistance
AT xujian disablinguncompetitiveinhibitionofoncogenicidhmutationsdrivesacquiredresistance