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)1,2,3,4,5,6,7,8. Enasidenib (AG-221) is an allosteric inhibitor that binds to the IDH2 dimer interface and blocks the production of 2HG by IDH2 mutants9,10. In a phase I/II clinical trial, enasidenib inhibited the production of 2HG and induced clinical responses in relapsed or refractory IDH2-mutant AML11. 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 disease alleles alone did not induce the production of 2HG; however, 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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We thank members of the Levine and Thompson laboratories for discussions. We thank W.K. Chatila and N. Schultz for assistance with data deposition. A.M.I. is supported by the NIH/NCI (K08 CA201483), Leukemia & Lymphoma Society (3356-16), Burroughs Wellcome Fund (1015584), Susan & Peter Solomon Divisional Genomics Program, Steven A. Greenberg Fund, and Cycle for Survival. A.H.S. is supported by the NIH/NCI (K08 CA181507) and Leukemia & Lymphoma Society. The work was also supported, in part, by the Conquer Cancer Foundation of ASCO (A.M.I., A.H.S. and J.T.), the Leukemia & Lymphoma Society Specialized Center of Research Program (7011-16; A.M.I. and C.B.T.), a Translational and Integrative Medicine Research Fund (TIMRF) grant (A.H.S. and E.M.S.), the American Association for Cancer Research (J.T.), the American Society of Hematology/Robert Woods Johnson Foundation (J.T.), and grants from the NIH, including R01 CA168802-02 (C.B.T.), R35 CA197594-01A1 (R.L.L.), U54 OD020355 (R.L.L.), and the Memorial Sloan Kettering Cancer Center Support Grant (NIH P30 CA008748) including a supplement to R.L.L., C.B.T. and A.H.S. We acknowledge the use of the Integrated Genomics Operation Core, funded by the Memorial Sloan Kettering Cancer Center Support Grant (NIH P30 CA008748), Cycle for Survival, and the Marie-Josée and Henry R. Kravis Center for Molecular Oncology.
Nature thanks J. Cortes and the other anonymous reviewer(s) for their contribution to the peer review of this work.