Disabling Uncompetitive Inhibition of Oncogenic IDH Mutations Drives Acquired Resistance

Junhua Lyu, Yuxuan Liu, Lihu Gong, Mingyi Chen, Yazan F. Madanat, Yuannyu Zhang, Feng Cai, Zhimin Gu, Hui Cao, Pranita Kaphle, Yoon Jung Kim, Fatma N. Kalkan, Helen Stephens, Kathryn E. Dickerson, Min Ni, Weina Chen, Prapti Patel, Alice S. Mims, Uma Borate, Amy BurdSheng F. Cai, C. Cameron Yin, M. James You, Stephen S. Chung, Robert H. Collins, Ralph J. Deberardinis, Xin Liu, Jian Xu

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)170-193
Number of pages24
JournalCancer discovery
Volume13
Issue number1
DOIs
StatePublished - Jan 1 2023

ASJC Scopus subject areas

  • Oncology

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