21598290cd180877-sup-supplementary_data.xlsx (65.69 kB)

Supplementary Data from Isoform Switching as a Mechanism of Acquired Resistance to Mutant Isocitrate Dehydrogenase Inhibition

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posted on 2023-04-03, 22:02 authored by James J. Harding, Maeve A. Lowery, Alan H. Shih, Juan M. Schvartzman, Shengqi Hou, Christopher Famulare, Minal Patel, Mikhail Roshal, Richard K. Do, Ahmet Zehir, Daoqi You, S. Duygu Selcuklu, Agnes Viale, Martin S. Tallman, David M. Hyman, Ed Reznik, Lydia W.S. Finley, Elli Papaemmanuil, Alessandra Tosolini, Mark G. Frattini, Kyle J. MacBeth, Guowen Liu, Bin Fan, Sung Choe, Bin Wu, Yelena Y. Janjigian, Ingo K. Mellinghoff, Luis A. Diaz, Ross L. Levine, Ghassan K. Abou-Alfa, Eytan M. Stein, Andrew M. Intlekofer

Next-generation sequencing and droplet digital PCR

Funding

NIH/NCI

Leukemia and Lymphoma Society

Burroughs Wellcome Fund

Damon Runyon Cancer Research Foundation

Leukemia and Lymphoma Society Specialized Center of Research Program

Translational and Integrative Medicine Research Fund

NIH

Memorial Sloan Kettering Cancer Center

Stand Up To Cancer Colorectal Cancer Dream Team Translational Research

Henry R. Kravis Center for Molecular Oncology

History

ARTICLE ABSTRACT

Somatic mutations in cytosolic or mitochondrial isoforms of isocitrate dehydrogenase (IDH1 or IDH2, respectively) contribute to oncogenesis via production of the metabolite 2-hydroxyglutarate (2HG). Isoform-selective IDH inhibitors suppress 2HG production and induce clinical responses in patients with IDH1- and IDH2-mutant malignancies. Despite the promising activity of IDH inhibitors, the mechanisms that mediate resistance to IDH inhibition are poorly understood. Here, we describe four clinical cases that identify mutant IDH isoform switching, either from mutant IDH1 to mutant IDH2 or vice versa, as a mechanism of acquired clinical resistance to IDH inhibition in solid and liquid tumors. IDH-mutant cancers can develop resistance to isoform-selective IDH inhibition by “isoform switching” from mutant IDH1 to mutant IDH2 or vice versa, thereby restoring 2HG production by the tumor. These findings underscore a role for continued 2HG production in tumor progression and suggest therapeutic strategies to prevent or overcome resistance.This article is highlighted in the In This Issue feature, p. 1494

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Keywords

Drug Mechanisms Cellular responses to anticancer drugs Drug Resistance Clinical drug resistance Novel mechanisms Gastrointestinal Cancers Liver cancer Hematological Cancers Leukemias Small Molecule Agents

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CC BY

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