RT Journal Article
SR Electronic
T1 Isoform switching as a mechanism of acquired resistance to isocitrate dehydrogenase inhibition
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 381954
DO 10.1101/381954
A1 James J. Harding
A1 Maeve A. Lowery
A1 Alan H. Shih
A1 Juan M. Schvartzman
A1 Shengqi Hou
A1 Christopher Famulare
A1 Minal Patel
A1 Mikhail Roshal
A1 Richard K. G. Do
A1 Ahmet Zehir
A1 Daoqi You
A1 S. Duygu Selcuklu
A1 Agnes Viale
A1 Martin S. Tallman
A1 David M. Hyman
A1 Ed Reznik
A1 Lydia W.S. Finley
A1 Elli Papaemmanuil
A1 Alessandra Tosolini
A1 Mark G. Frattini
A1 Kyle J. MacBeth
A1 Guowen Liu
A1 Bin Fan
A1 Sung Choe
A1 Bin Wu
A1 Yelena Y. Janjigian
A1 Ingo K. Mellinghoff
A1 Luis A. Diaz
A1 Ross L. Levine
A1 Ghassan K. Abou-Alfa
A1 Eytan M. Stein
A1 Andrew M. Intlekofer
YR 2018
UL http://biorxiv.org/content/early/2018/08/01/381954.abstract
AB 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 2-hydroxyglutarate (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.