Isoform switching as a mechanism of acquired resistance to mutant isocitrate dehydrogenase inhibition Journal Article


Authors: Harding, J. J.; Lowery, M. A.; Shih, A. H.; Schvartzman, J. M.; Hou, S.; Famulare, C.; Patel, M.; Roshal, M.; Do, R. K.; Zehir, A.; You, D.; Selcuklu, S. D.; Viale, A.; Tallman, M. S.; Hyman, D. M.; Reznik, E.; Finley, L. W. S.; Papaemmanuil, E.; Tosolini, A.; Frattini, M. G.; MacBeth, K. J.; Liu, G.; Fan, B.; Choe, S.; Wu, B.; Janjigian, Y. Y.; Mellinghoff, I. K.; Diaz, L. A.; Levine, R. L.; Abou-Alfa, G. K.; Stein, E. M.; Intlekofer, A. M.
Article Title: Isoform switching as a mechanism of acquired resistance to mutant isocitrate dehydrogenase inhibition
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. © 2018 AACR.
Keywords: adult; clinical article; aged; middle aged; gene mutation; somatic mutation; cancer recurrence; case report; drug withdrawal; gastrointestinal hemorrhage; cancer staging; follow up; polymerase chain reaction; anorexia; adenocarcinoma; computer assisted tomography; enzyme inhibition; multiple cycle treatment; genotype; cytogenetics; allogenic bone marrow transplantation; fever; hypoxia; hospitalization; myelodysplastic syndrome; fluorescence in situ hybridization; death; bone marrow biopsy; liver tumor; pancytopenia; clostridium difficile infection; cyclin dependent kinase inhibitor 2a; gene switching; drug dose increase; karyotype; lymphadenopathy; azacitidine; dysplasia; isocitrate dehydrogenase; dna methyltransferase 3a; isocitrate dehydrogenase 1; isoenzyme; cd135 antigen; nucleophosmin; acute myeloid leukemia; genetic resistance; body weight loss; next generation sequencing; stomach distension; isocitrate dehydrogenase 2; disease burden; human; male; female; article; pembrolizumab; enasidenib; ivosidenib; vorasidenib
Journal Title: Cancer Discovery
Volume: 8
Issue: 12
ISSN: 2159-8274
Publisher: American Association for Cancer Research  
Date Published: 2018-12-01
Start Page: 1540
End Page: 1547
Language: English
DOI: 10.1158/2159-8290.Cd-18-0877
PROVIDER: scopus c2 - 30355724
PUBMED: 30355724
PMCID: PMC6699636
DOI/URL:
Notes: Cancer Discov. -- Export Date: 2 January 2019 -- Article -- Source: Scopus C2 - 30355724
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Citation Impact
MSK Authors
  1. Eytan Moshe Stein
    154 Stein
  2. James Joseph Harding
    120 Harding
  3. Martin Stuart Tallman
    504 Tallman
  4. Ghassan Abou-Alfa
    328 Abou-Alfa
  5. Yelena Yuriy Janjigian
    200 Janjigian
  6. Alan H Shih
    56 Shih
  7. Maeve Aine Lowery
    132 Lowery
  8. Kinh Gian Do
    154 Do
  9. David Hyman
    321 Hyman
  10. Ross Levine
    546 Levine
  11. Agnes Viale
    217 Viale
  12. Ahmet Zehir
    227 Zehir
  13. Lydia Whitney Stillman Finley
    21 Finley
  14. Minal A Patel
    46 Patel
  15. Daoqi You
    27 You
  16. Eduard Reznik
    51 Reznik
  17. Mikhail Roshal
    100 Roshal
  18. Luis Alberto Diaz
    50 Diaz
  19. Shengqi Hou
    2 Hou