Author
Listed:
- Andrew M. Intlekofer
(Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center
Lymphoma Service, Memorial Sloan Kettering Cancer Center
Memorial Sloan Kettering Cancer Center)
- Alan H. Shih
(Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center
Memorial Sloan Kettering Cancer Center
Leukemia Service, Memorial Sloan Kettering Cancer Center)
- Bo Wang
(Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center
Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center)
- Abbas Nazir
(Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center)
- Ariën S. Rustenburg
(Computational & Systems Biology Program, Memorial Sloan Kettering Cancer Center)
- Steven K. Albanese
(Computational & Systems Biology Program, Memorial Sloan Kettering Cancer Center
Gerstner Sloan Kettering Graduate School, Memorial Sloan Kettering Cancer Center)
- Minal Patel
(Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center)
- Christopher Famulare
(Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center)
- Fabian M. Correa
(Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center)
- Naofumi Takemoto
(Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center)
- Vidushi Durani
(Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center)
- Hui Liu
(The Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center)
- Justin Taylor
(Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center
Memorial Sloan Kettering Cancer Center
Leukemia Service, Memorial Sloan Kettering Cancer Center)
- Noushin Farnoud
(Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center
Memorial Sloan Kettering Cancer Center
Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center)
- Elli Papaemmanuil
(Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center
Memorial Sloan Kettering Cancer Center
Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center)
- Justin R. Cross
(The Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center)
- Martin S. Tallman
(Memorial Sloan Kettering Cancer Center
Leukemia Service, Memorial Sloan Kettering Cancer Center)
- Maria E. Arcila
(Memorial Sloan Kettering Cancer Center)
- Mikhail Roshal
(Memorial Sloan Kettering Cancer Center)
- Gregory A. Petsko
(Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York)
- Bin Wu
(Agios Pharmaceuticals, Inc)
- Sung Choe
(Agios Pharmaceuticals, Inc)
- Zenon D. Konteatis
(Agios Pharmaceuticals, Inc)
- Scott A. Biller
(Agios Pharmaceuticals, Inc)
- John D. Chodera
(Computational & Systems Biology Program, Memorial Sloan Kettering Cancer Center)
- Craig B. Thompson
(Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center)
- Ross L. Levine
(Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center
Memorial Sloan Kettering Cancer Center
Leukemia Service, Memorial Sloan Kettering Cancer Center)
- Eytan M. Stein
(Memorial Sloan Kettering Cancer Center
Leukemia Service, Memorial Sloan Kettering Cancer Center)
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.
Suggested Citation
Andrew M. Intlekofer & Alan H. Shih & Bo Wang & Abbas Nazir & Ariën S. Rustenburg & Steven K. Albanese & Minal Patel & Christopher Famulare & Fabian M. Correa & Naofumi Takemoto & Vidushi Durani & Hui, 2018.
"Acquired resistance to IDH inhibition through trans or cis dimer-interface mutations,"
Nature, Nature, vol. 559(7712), pages 125-129, July.
Handle:
RePEc:nat:nature:v:559:y:2018:i:7712:d:10.1038_s41586-018-0251-7
DOI: 10.1038/s41586-018-0251-7
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Cited by:
- Raphael Reinbold & Ingvild C. Hvinden & Patrick Rabe & Ryan A. Herold & Alina Finch & James Wood & Melissa Morgan & Maximillian Staudt & Ian J. Clifton & Fraser A. Armstrong & James S. O. McCullagh & , 2022.
"Resistance to the isocitrate dehydrogenase 1 mutant inhibitor ivosidenib can be overcome by alternative dimer-interface binding inhibitors,"
Nature Communications, Nature, vol. 13(1), pages 1-12, December.
- Keith Woodley & Laura S. Dillingh & George Giotopoulos & Pedro Madrigal & Kevin M. Rattigan & Céline Philippe & Vilma Dembitz & Aoife M. S. Magee & Ryan Asby & Louie N. van de Lagemaat & Christopher M, 2023.
"Mannose metabolism inhibition sensitizes acute myeloid leukaemia cells to therapy by driving ferroptotic cell death,"
Nature Communications, Nature, vol. 14(1), pages 1-19, December.
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