Journal
CANCER DISCOVERY
Volume 8, Issue 12, Pages 1540-1547Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-18-0877
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Funding
- NIH/NCI [K08 CA181507, K08 CA201483]
- Leukemia and Lymphoma Society
- Burroughs Wellcome Fund [CAMS 1015584]
- Damon Runyon Cancer Research Foundation [CI 95-18]
- Leukemia and Lymphoma Society [3356-16]
- Susan and Peter Solomon Divisional Genomics Program
- Steven A. Greenberg Fund
- Cycle for Survival
- Leukemia and Lymphoma Society Specialized Center of Research Program [7011-16]
- Translational and Integrative Medicine Research Fund (TIMRF) grant
- NIH [R35 CA197594-01A1, U54 OD020355]
- Memorial Sloan Kettering Cancer Center Support Grant [NIHP30 CA008748]
- Stand Up To Cancer Colorectal Cancer Dream Team Translational Research Grant [SU2C-AACR-DT22-17]
- American Association for Cancer Research
- Marie-Josee and Henry R. Kravis Center for Molecular Oncology
- NATIONAL CANCER INSTITUTE [P30CA008748, K08CA181507, K08CA201483, R35CA197594] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R35NS105109] Funding Source: NIH RePORTER
- OFFICE OF THE DIRECTOR, NATIONAL INSTITUTES OF HEALTH [U54OD020355] Funding Source: NIH RePORTER
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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. (C) 2018 AACR.
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