Acquired resistance to IDH inhibition through trans or cis dimer-interface mutations

Andrew M. Intlekofer, Alan H. Shih, Bo Wang, Abbas Nazir, Ariën S. Rustenburg, Steven K. Albanese, Minal Patel, Christopher Famulare, Fabian M. Correa, Naofumi Takemoto, Vidushi Durani, Hui Liu, Justin Taylor, Noushin Farnoud, Elli Papaemmanuil, Justin R. Cross, Martin S. Tallman, Maria E. Arcila, Mikhail Roshal, Gregory A. Petsko, Bin Wu, Sung Choe, Zenon D. Konteatis, Scott A. Biller, John D. Chodera, Craig B. Thompson (), Ross L. Levine () and Eytan M. Stein ()
Additional contact information
Andrew M. Intlekofer: Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Alan H. Shih: Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Bo Wang: Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Abbas Nazir: Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Ariën S. Rustenburg: Computational & Systems Biology Program, Memorial Sloan Kettering Cancer Center
Steven K. Albanese: Computational & Systems Biology Program, Memorial Sloan Kettering Cancer Center
Minal Patel: Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center
Christopher Famulare: Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center
Fabian M. Correa: Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Naofumi Takemoto: Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Vidushi Durani: Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Hui Liu: The Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center
Justin Taylor: Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Noushin Farnoud: Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center
Elli Papaemmanuil: Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center
Justin R. Cross: The Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center
Martin S. Tallman: Memorial Sloan Kettering Cancer Center
Maria E. Arcila: Memorial Sloan Kettering Cancer Center
Mikhail Roshal: Memorial Sloan Kettering Cancer Center
Gregory A. Petsko: Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York
Bin Wu: Agios Pharmaceuticals, Inc
Sung Choe: Agios Pharmaceuticals, Inc
Zenon D. Konteatis: Agios Pharmaceuticals, Inc
Scott A. Biller: Agios Pharmaceuticals, Inc
John D. Chodera: Computational & Systems Biology Program, Memorial Sloan Kettering Cancer Center
Craig B. Thompson: Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center
Ross L. Levine: Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Eytan M. Stein: Memorial Sloan Kettering Cancer Center

Nature, 2018, vol. 559, issue 7712, 125-129

Abstract: Abstract 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 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.

Date: 2018
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DOI: 10.1038/s41586-018-0251-7

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