Journal Article

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

Nazir, Abbas, Arcila, Maria E., Tallman, Martin S., Takemoto, Naofumi, Petsko, Gregory A., Biller, Scott A., Konteatis, Zenon D., Wu, Bin, Correa, Fabian M., Liu, Hui, Roshal, Mikhail, Thompson, Craig B., Farnoud, Noushin, Chodera, John D., Famulare, Christopher, Papaemmanuil, Elli, Cross, Justin R., Rustenburg, Ariën S., Taylor, Justin, Levine, Ross L., Patel, Minal, Wang, Bo, Stein, Eytan M., Durani, Vidushi, Intlekofer, Andrew M., Choe, Sung, Shih, Alan H., Albanese, Steven K.

2018

Overview

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 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. A new mechanism of acquired clinical resistance in two patients with acute myeloid leukaemia driven by mutant IDH2 is described, in which a second-site mutation on the wild-type allele induces therapeutic resistance to IDH2 inhibitors.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 101/58 / 13/1 / 13/106 / 13/109 / 13/31 / 38/22 / 38/23 / 38/77 / 38/90 / 42/44 / 631/67/1059/2326 / 631/67/1990/283/1897 / 631/67/2327 / 64/110 / 64/60 / 82/16 / 82/29 / 82/80 / 82/83 / Acute myeloid leukemia / Alleles / Allosteric properties / Allosteric Site - drug effects / Allosteric Site - genetics / Aminopyridines - chemistry / Aminopyridines - pharmacology / Aminopyridines - therapeutic use / Animals / Antineoplastic agents / Bone marrow / Cancer therapies / Cisgender / Clinical Trials, Phase I as Topic / Clinical Trials, Phase II as Topic / Cloning / Decitabine / Dimers / Disease Progression / Disease resistance / Drug resistance / Drug Resistance, Neoplasm - drug effects / Drug Resistance, Neoplasm - genetics / Enzyme Inhibitors - chemistry / Enzyme Inhibitors - pharmacology / Enzyme Inhibitors - therapeutic use / Female / Genes / Glutamine / Glutamine - genetics / Glutarates - blood / Glutarates - metabolism / HEK293 Cells / Humanities and Social Sciences / Humans / Inhibitors / Isocitrate dehydrogenase / Isocitrate Dehydrogenase - antagonists & inhibitors / Isocitrate Dehydrogenase - genetics / Isoleucine / Isoleucine - genetics / Kinases / Letter / Leukemia / Leukemia, Myeloid, Acute - blood / Leukemia, Myeloid, Acute - drug therapy / Leukemia, Myeloid, Acute - genetics / Lung cancer / Mice / Mice, Inbred C57BL / Models, Molecular / multidisciplinary / Mutant Proteins - antagonists & inhibitors / Mutant Proteins - genetics / Mutants / Mutation / Neutropenia / Neutrophils / Pathogenesis / Patients / Pharmaceutical research / Plasma / Protein Multimerization - genetics / Proteins / Science / Science (multidisciplinary) / Target acquisition / Triazines - chemistry / Triazines - pharmacology / Triazines - therapeutic use