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Ref Type Journal Article
PMID (36222845)
Authors Lyu J, Liu Y, Gong L, Chen M, Madanat YF, Zhang Y, Cai F, Gu Z, Cao H, Kaphle P, Kim YJ, Kalkan FN, Stephens H, Dickerson KE, Ni M, Chen W, Patel P, Mims AS, Borate U, Burd A, Cai SF, Yin CC, You MJ, Chung SS, Collins RH, DeBerardinis RJ, Liu X, Xu J
Title Disabling Uncompetitive Inhibition of Oncogenic IDH Mutations Drives Acquired Resistance.
Journal Vol Issue Date Pages Journal Short Title
Cancer discovery 13 1 2023 Jan 09 170-193 Cancer Discov
URL
Abstract Text 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.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.

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