TY - JOUR
T1 - Isoform switching as a mechanism of acquired resistance to mutant isocitrate dehydrogenase inhibition
AU - Harding, James J.
AU - Lowery, Maeve A.
AU - Shih, Alan H.
AU - Schvartzman, Juan M.
AU - Hou, Shengqi
AU - Famulare, Christopher
AU - Patel, Minal
AU - Roshal, Mikhail
AU - Do, Richard K.
AU - Zehir, Ahmet
AU - You, Daoqi
AU - Selcuklu, S. Duygu
AU - Viale, Agnes
AU - Tallman, Martin S.
AU - Hyman, David M.
AU - Reznik, Ed
AU - Finley, Lydia W.S.
AU - Papaemmanuil, Elli
AU - Tosolini, Alessandra
AU - Frattini, Mark G.
AU - Macbeth, Kyle J.
AU - Liu, Guowen
AU - Fan, Bin
AU - Choe, Sung
AU - Wu, Bin
AU - Janjigian, Yelena Y.
AU - Mellinghoff, Ingo K.
AU - Diaz, Luis A.
AU - Levine, Ross L.
AU - Abou-Alfa, Ghassan K.
AU - Stein, Eytan M.
AU - Intlekofer, Andrew M.
N1 - Publisher Copyright:
© 2018 AACR.
PY - 2018/12
Y1 - 2018/12
N2 - 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.
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 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.
UR - https://www.scopus.com/pages/publications/85058056463
U2 - 10.1158/2159-8290.CD-18-0877
DO - 10.1158/2159-8290.CD-18-0877
M3 - Article
C2 - 30355724
AN - SCOPUS:85058056463
SN - 2159-8274
VL - 8
SP - 1540
EP - 1546
JO - Cancer Discovery
JF - Cancer Discovery
IS - 12
ER -