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

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

doi:10.1038/s41586-018-0251-7

Cited by 281Acute Myeloid Leukemia ResearchGlioma Diagnosis and TreatmentCancer Genomics and Diagnostics

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

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Intlekofer, Andrew M., Shih, Alan H., Wang, Bo, Nazir, Abbas, Rustenburg, Ariën S., Albanese, Steven K., Patel, Minal, Famulare, Christopher +20 more·2018·Nature

DOI 10.1038/s41586-018-0251-7PMC PMC6121718

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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 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.

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Metabolic alterations can cause global perturbations of the epigenome.
“Therefore, metabolic alterations can induce global perturbations of the epigenome and mutant metabolic components represent potential therapeutic targets 83,84 .”
From Advances in epigenetics link genetics to the environment and disease (2019) · cites this paper as [83]

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The Molecular Mechanisms of Resistance to IDH Inhibitors in Acute Myeloid Leukemia
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Second-Site IDH2 Mutations Confer Resistance to Enasidenib In Trans
(2018) · Cancer Discovery · doi:10.1158/2159-8290.cd-rw2018-114

Authors: Intlekofer, A. M., Shih, A. H., Wang, B., Nazir, A., Rustenburg, A. S., Albanese, S. K., Patel, M., Famulare, C., Correa, F. M., Takemoto, N., Durani, V., Liu, H., Taylor, J., Farnoud, N., Papaemmanuil, E., Cross, J. R., Tallman, M. S., Arcila, M. E., Roshal, M., Petsko, G. A., Wu, B., Choe, S., Konteatis, Z. D., Biller, S. A., Chodera, J. D., Thompson, C. B., Levine, R. L., & Stein, E. M.
Affiliations: Memorial Sloan Kettering Cancer Center (US)
Weill Cornell Medicine (US)
Agios Pharmaceuticals (United States) (US)
Corresponding author: Thompson, Craig B.
Levine, Ross L.
Stein, Eytan M.
ORCID: Intlekofer, Andrew M.
Shih, Alan H.
Wang, Bo
Nazir, Abbas
Rustenburg, Ariën S.
Albanese, Steven K.
Famulare, Christopher
Durani, Vidushi
Liu, Hui
Taylor, Justin
Farnoud, Noushin
Papaemmanuil, Elli
Cross, Justin R.
Tallman, Martin S.
Arcila, Maria E.
Roshal, Mikhail
Petsko, Gregory A.
Wu, Bin
Choe, Sung
Konteatis, Zenon D.
Chodera, John D.
Thompson, Craig B.
Levine, Ross L.
Stein, Eytan M.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2018-06-27
Volume: 559
Issue: 7712
Pages: 125-129
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/s41586-018-0251-7
PMC: PMC6121718
OpenAlex: W2810336146
Cited by: 281
References: 24
Citations by year: 2026: 14 · 2025: 21 · 2024: 26 · 2023: 28 · 2022: 38 · 2021: 58 · 2020: 40 · 2019: 42 · 2018: 11
FWCI: 27.07
Type: journal article
Language: en
Open access: green
europepmc.org
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Funders: National Institutes of Health (U54OD020355)
National Cancer Institute (K08CA181507, K08CA201483, R01CA168802, P30CA008748, R35CA197594)
Topics: Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Keywords: IDH2 mutation, acute myeloid leukemia, enasidenib, ivosidenib, acquired drug resistance, 2-hydroxyglutarate, second-site mutations, oncometabolites, targeted therapy resistance
MeSH terms: Alleles, Allosteric Site, Aminopyridines, Animals, Enzyme Inhibitors, Female, Glutamine, Glutarates, Humans, Isocitrate Dehydrogenase, Isoleucine, Mice, Inbred C57BL, Models, Molecular, Mutation, Triazines, Leukemia, Myeloid, Acute, Clinical Trials, Phase I as Topic, Clinical Trials, Phase II as Topic, Disease Progression, Drug Resistance, Neoplasm, Mutant Proteins, Mice, Protein Multimerization, HEK293 Cells

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

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