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Ref Type Journal Article
PMID (29950729)
Authors Intlekofer AM, Shih AH, Wang B, Nazir A, Rustenburg AS, Albanese SK, Patel M, Famulare C, Correa FM, Takemoto N, Durani V, Liu H, Taylor J, Farnoud N, Papaemmanuil E, Cross JR, Tallman MS, Arcila ME, Roshal M, Petsko GA, Wu B, Choe S, Konteatis ZD, Biller SA, Chodera JD, Thompson CB, Levine RL, Stein EM
Title Acquired resistance to IDH inhibition through trans or cis dimer-interface mutations.
Journal Nature
Vol 559
Issue 7712
Date 2018 Jul
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
IDH1 S280F missense unknown IDH1 S280F does not lie within any known functional domains of the Idh1 protein (UniProt.org). S280F has been associated with acquired resistance to IDH inhibitors when occurred in cis with IDH1 R132C in a patient (PMID: 29950729), but has not been biochemically characterized and therefore, its effect on Idh1 protein function is unknown (PubMed, Sep 2020). Y
IDH2 I319M missense no effect - predicted IDH2 I319M does not lie within any known functional domains of the Idh2 protein (UniPort.org). I319M demonstrates dimerization ability and does not lead to increased production of 2HG in culture similar to wild-type Idh2, however, is associated with resistance to Enasidenib when occurring in cis or trans with IDH2 R140Q (PMID: 29950729). Y
IDH2 Q316E missense no effect - predicted IDH2 Q316E does not lie within any known functional domains of the Idh2 protein (UniPort.org). Q316E demonstrates dimerization ability and does not lead to increased production of 2HG in culture similar to wild-type Idh2, however, is associated with resistance to Enasidenib when occurring in cis or trans with IDH2 R140Q (PMID: 29950729). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
IDH1 R132C IDH1 S280F acute myeloid leukemia predicted - resistant Ivosidenib Case Reports/Case Series Actionable In a clinical study, IDH1 S280F was identified as an acquired mutation in cis with the original IDH1 R132C in a patient with acute myeloid leukemia (AML), who developed resistance to Tibsovo (ivosidenib) after initial response (PMID: 29950729). 29950729
IDH2 R140Q IDH2 I319M acute myeloid leukemia resistant Enasidenib Case Reports/Case Series Actionable In a clinical study, IDH2 I319M was identified as an acquired mutation in trans with the original IDH2 R140Q in a patient with acute myeloid leukemia (AML), who developed resistance to Idhifa (enasidenib) after initial response, and coexpression of IDH2 I319M in trans or in cis with IDH2 R140Q conferred resistance to Idhifa (enasidenib) in culture, supporting a mechanism of variants cooperating to confer resistance (PMID: 29950729). 29950729
IDH2 R140Q IDH2 Q316E acute myeloid leukemia resistant Enasidenib Case Reports/Case Series Actionable In a clinical study, IDH2 Q316E was identified as an acquired mutation in trans with the original IDH2 R140Q in a patient with acute myeloid leukemia (AML), who developed resistance to Idhifa (enasidenib) after initial response, and coexpression of IDH2 Q316E in trans or in cis with IDH2 R140Q conferred resistance to Idhifa (enasidenib) in culture and in animal models of AML, supporting a mechanism of variants cooperating to confer resistance (PMID: 29950729). 29950729