Journal
NATURE
Volume 559, Issue 7712, Pages 125-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41586-018-0251-7
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Funding
- NIH/NCI [K08 CA201483, K08 CA181507]
- Leukemia & Lymphoma Society [3356-16]
- Burroughs Wellcome Fund [1015584]
- Susan & Peter Solomon Divisional Genomics Program
- Steven A. Greenberg Fund
- Cycle for Survival
- Leukemia & Lymphoma Society
- Conquer Cancer Foundation of ASCO
- Leukemia & Lymphoma Society Specialized Center of Research Program [7011-16]
- Translational and Integrative Medicine Research Fund (TIMRF) grant
- American Association for Cancer Research
- American Society of Hematology/Robert Woods Johnson Foundation
- NIH [R01 CA16880202, R35 CA197594-01A1, U54 OD020355]
- Memorial Sloan Kettering Cancer Center (NIH) [P30 CA008748]
- Marie-Josee and Henry R. Kravis Center for Molecular Oncology
- NATIONAL CANCER INSTITUTE [K08CA201483, R35CA197594, R01CA168802, K08CA181507, P30CA008748] Funding Source: NIH RePORTER
- OFFICE OF THE DIRECTOR, NATIONAL INSTITUTES OF HEALTH [U54OD020355] Funding Source: NIH RePORTER
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Somatic mutations in the isocitrate dehydrogenase 2 gene (IDH2) contribute to the pathogenesis of acute myeloid leukaemia (AML) through the production of the oncometabolite 2-hydroxyglutarate (2HG)(1-8). Enasidenib (AG-221) is an allosteric inhibitor that binds to the IDH2 dimer interface and blocks the production of 2HG by IDH2 mutants(9,10). In a phase I/II clinical trial, enasidenib inhibited the production of 2HG and induced clinical responses in relapsed or refractory IDH2-mutant AML(11). Here we describe two patients with IDH2-mutant AML who had a clinical response to enasidenib followed by clinical resistance, disease progression, and a recurrent increase in circulating levels of 2HG. We show that therapeutic resistance is associated with the emergence of second-site IDH2 mutations in trans, such that the resistance mutations occurred in the IDH2 allele without the neomorphic R140Q mutation. The in trans mutations occurred at glutamine 316 (Q316E) and isoleucine 319 (I319M), which are at the interface where enasidenib binds to the IDH2 dimer. The expression of either of these mutant the expression of the Q316E or I319M mutation together with the R140Q mutation in trans allowed 2HG production that was resistant to inhibition by enasidenib. Biochemical studies predicted that resistance to allosteric IDH inhibitors could also occur via IDH dimer-interface mutations in cis, which was confirmed in a patient with acquired resistance to the IDH1 inhibitor ivosidenib (AG-120). Our observations uncover a mechanism of acquired resistance to a targeted therapy and underscore the importance of 2HG production in the pathogenesis of IDH-mutant malignancies.
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