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 |
| PUBMED: | 30355724 |
| PMCID: | PMC6699636 |
| DOI/URL: | |
| Notes: | Cancer Discov. -- Export Date: 2 January 2019 -- Article -- Source: Scopus C2 - 30355724 |
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