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Nature. 2018 Jul;559(7712):125-129. doi: 10.1038/s41586-018-0251-7. Epub 2018 Jun 27.

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

Author information

1
Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
2
Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
3
Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
4
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
5
Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
6
Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
7
Computational & Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
8
Gerstner Sloan Kettering Graduate School, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
9
The Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
10
Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
11
Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
12
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
13
Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York, USA.
14
Agios Pharmaceuticals, Inc, Cambridge, MA, USA.
15
Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. thompsonc@mskcc.org.
16
Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. leviner@mskcc.org.
17
Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA. leviner@mskcc.org.
18
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. leviner@mskcc.org.
19
Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. leviner@mskcc.org.
20
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. steine@mskcc.org.
21
Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. steine@mskcc.org.

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.

PMID:
29950729
PMCID:
PMC6121718
DOI:
10.1038/s41586-018-0251-7
[Indexed for MEDLINE]
Free PMC Article

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