Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Nature	559	7712	2018 Jul	125-129	Nature

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	no effect - predicted	IDH1 S280F does not lie within any known functional domains of the Idh1 protein (UniProt.org). S280F confers resistance to an IDH1 inhibitor in the presence of IDH1 R132C/H (PMID: 29950729, PMID: 32380538, PMID: 36222845), but does not lead to increased production of the oncometabolite 2HG (R(-)-2-hydroxyglutarate) in cell culture (PMID: 36222845), and therefore, is predicted to have no effect on Idh1 protein function.	Y
IDH2	I319M	missense	no effect - predicted	IDH2 I319M does not lie within any known functional domains of the Idh2 protein (UniPort.org). I319M confers resistance to an IDH2 inhibitor in the presence of IDH2 R140Q, but retains dimerization ability and does not lead to increased production of 2HG in culture (PMID: 29950729, PMID: 36222845), and therefore, is predicted to have no effect on Idh2 protein function.	Y
IDH2	Q316E	missense	no effect - predicted	IDH2 Q316E does not lie within any known functional domains of the Idh2 protein (UniPort.org). Q316E confers resistance to an IDH2 inhibitor in the presence of IDH2 R140Q, but retains dimerization ability and does not lead to increased production of the oncometabolite 2HG (R(-)-2-hydroxyglutarate) in cell culture (PMID: 29950729, PMID: 36222845), and therefore, is predicted to have no effect on Idh2 protein function.	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