| Literature DB >> 30355724 |
James J Harding1,2, Maeve A Lowery1,2, Alan H Shih2,3,4,5, Juan M Schvartzman1,2, Shengqi Hou3,5, Christopher Famulare5, Minal Patel5, Mikhail Roshal6, Richard K Do7, Ahmet Zehir8, Daoqi You8, S Duygu Selcuklu8, Agnes Viale8, Martin S Tallman2,4, David M Hyman2,9,10, Ed Reznik11, Lydia W S Finley12,13, Elli Papaemmanuil5,8,11, Alessandra Tosolini14, Mark G Frattini14, Kyle J MacBeth14, Guowen Liu15, Bin Fan15, Sung Choe15, Bin Wu15, Yelena Y Janjigian1,2, Ingo K Mellinghoff3,16, Luis A Diaz2,17, Ross L Levine2,3,4,5, Ghassan K Abou-Alfa1,2, Eytan M Stein18,4, Andrew M Intlekofer18,3,5,19.
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. SIGNIFICANCE: 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. ©2018 American Association for Cancer Research.Entities:
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Year: 2018 PMID： 30355724 PMCID： PMC6699636 DOI： 10.1158/2159-8290.CD-18-0877
Source DB: PubMed Journal: Cancer Discov ISSN： 2159-8274 Impact factor: 38.272