Isoform Switching as a Mechanism of Acquired Resistance to Mutant Isocitrate Dehydrogenase Inhibition
Somatic mutations in cytosolic or mitochondrial isoforms of isocitrate dehydrogenase ( or , respectively) contribute to oncogenesis via production of the metabolite 2-hydroxyglutarate (2HG). Isoform-selective IDH inhibitors suppress 2HG production and induce clinical responses in patients with - and...
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| Published in | Cancer discovery Vol. 8; no. 12; pp. 1540 - 1547 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
01.12.2018
|
| Subjects | |
| Online Access | Get full text |
| ISSN | 2159-8274 2159-8290 2159-8290 |
| DOI | 10.1158/2159-8290.CD-18-0877 |
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| Abstract | Somatic mutations in cytosolic or mitochondrial isoforms of isocitrate dehydrogenase (
or
, respectively) contribute to oncogenesis via production of the metabolite 2-hydroxyglutarate (2HG). Isoform-selective IDH inhibitors suppress 2HG production and induce clinical responses in patients with
- and
-mutant malignancies. Despite the promising activity of IDH inhibitors, the mechanisms that mediate resistance to IDH inhibition are poorly understood. Here, we describe four clinical cases that identify mutant IDH isoform switching, either from mutant IDH1 to mutant IDH2 or vice versa, as a mechanism of acquired clinical resistance to IDH inhibition in solid and liquid tumors. SIGNIFICANCE: IDH-mutant cancers can develop resistance to isoform-selective IDH inhibition by "isoform switching" from mutant IDH1 to mutant IDH2 or vice versa, thereby restoring 2HG production by the tumor. These findings underscore a role for continued 2HG production in tumor progression and suggest therapeutic strategies to prevent or overcome resistance.
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| AbstractList | Somatic mutations in cytosolic or mitochondrial isoforms of isocitrate dehydrogenase (
or
, respectively) contribute to oncogenesis via production of the metabolite 2-hydroxyglutarate (2HG). Isoform-selective IDH inhibitors suppress 2HG production and induce clinical responses in patients with
- and
-mutant malignancies. Despite the promising activity of IDH inhibitors, the mechanisms that mediate resistance to IDH inhibition are poorly understood. Here, we describe four clinical cases that identify mutant IDH isoform switching, either from mutant IDH1 to mutant IDH2 or vice versa, as a mechanism of acquired clinical resistance to IDH inhibition in solid and liquid tumors. SIGNIFICANCE: IDH-mutant cancers can develop resistance to isoform-selective IDH inhibition by "isoform switching" from mutant IDH1 to mutant IDH2 or vice versa, thereby restoring 2HG production by the tumor. These findings underscore a role for continued 2HG production in tumor progression and suggest therapeutic strategies to prevent or overcome resistance.
. Somatic mutations in cytosolic or mitochondrial isoforms of isocitrate dehydrogenase (IDH1 or IDH2, respectively) contribute to oncogenesis via production of the metabolite 2-hydroxyglutarate (2HG). Isoform-selective IDH inhibitors suppress 2HG production and induce clinical responses in patients with IDH1- and IDH2-mutant malignancies. Despite the promising activity of IDH inhibitors, the mechanisms that mediate resistance to IDH inhibition are poorly understood. Here, we describe four clinical cases that identify mutant IDH isoform switching, either from mutant IDH1 to mutant IDH2 or vice versa, as a mechanism of acquired clinical resistance to IDH inhibition in solid and liquid tumors. SIGNIFICANCE: IDH-mutant cancers can develop resistance to isoform-selective IDH inhibition by "isoform switching" from mutant IDH1 to mutant IDH2 or vice versa, thereby restoring 2HG production by the tumor. These findings underscore a role for continued 2HG production in tumor progression and suggest therapeutic strategies to prevent or overcome resistance.This article is highlighted in the In This Issue feature, p. 1494.Somatic mutations in cytosolic or mitochondrial isoforms of isocitrate dehydrogenase (IDH1 or IDH2, respectively) contribute to oncogenesis via production of the metabolite 2-hydroxyglutarate (2HG). Isoform-selective IDH inhibitors suppress 2HG production and induce clinical responses in patients with IDH1- and IDH2-mutant malignancies. Despite the promising activity of IDH inhibitors, the mechanisms that mediate resistance to IDH inhibition are poorly understood. Here, we describe four clinical cases that identify mutant IDH isoform switching, either from mutant IDH1 to mutant IDH2 or vice versa, as a mechanism of acquired clinical resistance to IDH inhibition in solid and liquid tumors. SIGNIFICANCE: IDH-mutant cancers can develop resistance to isoform-selective IDH inhibition by "isoform switching" from mutant IDH1 to mutant IDH2 or vice versa, thereby restoring 2HG production by the tumor. These findings underscore a role for continued 2HG production in tumor progression and suggest therapeutic strategies to prevent or overcome resistance.This article is highlighted in the In This Issue feature, p. 1494. Somatic mutations in cytosolic or mitochondrial isoforms of isocitrate dehydrogenase ( IDH1 or IDH2 , respectively) contribute to oncogenesis via production of the metabolite 2-hydroxyglutarate (2HG). Isoform-selective IDH inhibitors suppress 2HG production and induce clinical responses in patients with IDH1 - and IDH2 -mutant malignancies. Despite the promising activity of IDH inhibitors, the mechanisms that mediate resistance to IDH inhibition are poorly understood. Here, we describe four clinical cases that identify mutant IDH isoform switching, either from mutant IDH1 to mutant IDH2 or vice versa, as a mechanism of acquired clinical resistance to IDH inhibition in solid and liquid tumors. |
| Author | You, Daoqi Hou, Shengqi Selcuklu, S. Duygu Tallman, Martin S. Do, Richard K. Zehir, Ahmet Wu, Bin Liu, Guowen Janjigian, Yelena Y. Finley, Lydia W.S. Roshal, Mikhail Fan, Bin Diaz, Luis A. Lowery, Maeve A. Tosolini, Alessandra Schvartzman, Juan M. Frattini, Mark G. Famulare, Christopher Papaemmanuil, Elli Mellinghoff, Ingo K. Viale, Agnes MacBeth, Kyle J. Levine, Ross L. Patel, Minal Stein, Eytan M. Harding, James J. Reznik, Ed Abou-Alfa, Ghassan K. Choe, Sung Intlekofer, Andrew M. Hyman, David M. Shih, Alan H. |
| AuthorAffiliation | 4 Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, New York 9 Gynecologic Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York 16 Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York 17 Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, New York 7 Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York 5 Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, New York 14 Celgene Corporation, Summit, New Jersey 3 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 6 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 15 Agios Pharmaceuticals, Inc., Cambridge, Massachusetts 12 Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10 Early Drug Development Service, Memorial Sloan Kettering Cancer Center, New York, New York 8 |
| AuthorAffiliation_xml | – name: 5 Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, New York – name: 7 Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York – name: 13 Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York – name: 4 Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, New York – name: 11 Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York – name: 18 Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, New York – name: 2 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York – name: 9 Gynecologic Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York – name: 6 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York – name: 17 Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, New York – name: 10 Early Drug Development Service, Memorial Sloan Kettering Cancer Center, New York, New York – name: 12 Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York – name: 3 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York – name: 15 Agios Pharmaceuticals, Inc., Cambridge, Massachusetts – name: 16 Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York – name: 1 Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York – name: 14 Celgene Corporation, Summit, New Jersey – name: 8 Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York |
| Author_xml | – sequence: 1 givenname: James J. surname: Harding fullname: Harding, James J. – sequence: 2 givenname: Maeve A. surname: Lowery fullname: Lowery, Maeve A. – sequence: 3 givenname: Alan H. surname: Shih fullname: Shih, Alan H. – sequence: 4 givenname: Juan M. orcidid: 0000-0002-8036-1361 surname: Schvartzman fullname: Schvartzman, Juan M. – sequence: 5 givenname: Shengqi surname: Hou fullname: Hou, Shengqi – sequence: 6 givenname: Christopher surname: Famulare fullname: Famulare, Christopher – sequence: 7 givenname: Minal surname: Patel fullname: Patel, Minal – sequence: 8 givenname: Mikhail surname: Roshal fullname: Roshal, Mikhail – sequence: 9 givenname: Richard K. orcidid: 0000-0002-6554-0310 surname: Do fullname: Do, Richard K. – sequence: 10 givenname: Ahmet orcidid: 0000-0001-5406-4104 surname: Zehir fullname: Zehir, Ahmet – sequence: 11 givenname: Daoqi surname: You fullname: You, Daoqi – sequence: 12 givenname: S. Duygu surname: Selcuklu fullname: Selcuklu, S. Duygu – sequence: 13 givenname: Agnes surname: Viale fullname: Viale, Agnes – sequence: 14 givenname: Martin S. surname: Tallman fullname: Tallman, Martin S. – sequence: 15 givenname: David M. surname: Hyman fullname: Hyman, David M. – sequence: 16 givenname: Ed orcidid: 0000-0002-6511-5947 surname: Reznik fullname: Reznik, Ed – sequence: 17 givenname: Lydia W.S. orcidid: 0000-0003-4023-7574 surname: Finley fullname: Finley, Lydia W.S. – sequence: 18 givenname: Elli surname: Papaemmanuil fullname: Papaemmanuil, Elli – sequence: 19 givenname: Alessandra surname: Tosolini fullname: Tosolini, Alessandra – sequence: 20 givenname: Mark G. surname: Frattini fullname: Frattini, Mark G. – sequence: 21 givenname: Kyle J. surname: MacBeth fullname: MacBeth, Kyle J. – sequence: 22 givenname: Guowen surname: Liu fullname: Liu, Guowen – sequence: 23 givenname: Bin surname: Fan fullname: Fan, Bin – sequence: 24 givenname: Sung surname: Choe fullname: Choe, Sung – sequence: 25 givenname: Bin surname: Wu fullname: Wu, Bin – sequence: 26 givenname: Yelena Y. surname: Janjigian fullname: Janjigian, Yelena Y. – sequence: 27 givenname: Ingo K. surname: Mellinghoff fullname: Mellinghoff, Ingo K. – sequence: 28 givenname: Luis A. surname: Diaz fullname: Diaz, Luis A. – sequence: 29 givenname: Ross L. surname: Levine fullname: Levine, Ross L. – sequence: 30 givenname: Ghassan K. orcidid: 0000-0002-1522-8054 surname: Abou-Alfa fullname: Abou-Alfa, Ghassan K. – sequence: 31 givenname: Eytan M. surname: Stein fullname: Stein, Eytan M. – sequence: 32 givenname: Andrew M. surname: Intlekofer fullname: Intlekofer, Andrew M. |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/30355724$$D View this record in MEDLINE/PubMed |
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| Notes | ObjectType-Case Study-2 SourceType-Scholarly Journals-1 ObjectType-Feature-4 content type line 23 ObjectType-Report-1 ObjectType-Article-3 Authors’ Contributions Conception and design: J.J. Harding, M.A. Lowery, A.H. Shih, Y.Y. Janjigian, L.A. Diaz, R.L. Levine, G.K. Abou-Alfa, E.M. Stein, A.M. Intlekofer Writing, review, and/or revision of the manuscript: J.J. Harding, M.A. Lowery, A.H. Shih, J.M. Schvartzman, S. Hou, R.K. Do, A. Zehir S.D. Selcuklu, M.S. Tallman, D.M. Hyman, E. Reznik, L.W.S. Finley, M.G. Frattini, K.J. MacBeth, G. Liu, B. Fan, B. Wu, Y.Y. Janjigian I.K. Mellinghoff, L.A. Diaz, R.L. Levine, G.K. Abou-Alfa, E.M. Stein, A.M. Intlekofer Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): J.J. Harding, MA. Lowery, A.H. Shih, J.M. Schvartzman, S. Hou, C. Famulare, M. Patel, M. Roshal, R.K. Do Present address for M.A. Lowery: Trinity St. James Cancer Institute, Trinity College, Dublin, Ireland. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): J.J. Harding, M.A. Lowery, J.M. Schvartzman, S. Hou, A. Zehir, D. You, E. Reznik, E. Papaemmanuil, K.J. MacBeth, B. Fan, S. Choe, B. Wu, Y.Y. Janjigian, I.K. Mellinghoff, L.A. Diaz, G.K. Abou-Alfa, E.M. Stein, A.M. Intlekofer Study supervision: M.A. Lowery, A. Tosolini, M.G. Frattini, Y.Y. Janjigian, G.K. Abou-Alfa, E.M. Stein, A.M. Intlekofer A. Zehir, D. You, A. Viale, A. Tosolini, M.G. Frattini, K.J. MacBeth, G. Liu, B. Wu, I.K. Mellinghoff, G.K. Abou-Alfa, E.M. Stein, A.M. Indekofer Development of methodology: A.H. Shih, D. You, G.K. Abou-Alfa, E.M. Stein, A.M. Intlekofer Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): J.J. Harding, C. Famulare, M. Patel, M. Roshal, S.D. Selcuklu, D.M. Hyman, Y.Y. Janjigian, A.M. Intlekofer E.M. Stein and A.M. Intlekofer jointly supervised this work. |
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| PublicationDate | 2018-12-01 |
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| PublicationTitle | Cancer discovery |
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| PublicationYear | 2018 |
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| Snippet | Somatic mutations in cytosolic or mitochondrial isoforms of isocitrate dehydrogenase (
or
, respectively) contribute to oncogenesis via production of the... Somatic mutations in cytosolic or mitochondrial isoforms of isocitrate dehydrogenase (IDH1 or IDH2, respectively) contribute to oncogenesis via production of... Somatic mutations in cytosolic or mitochondrial isoforms of isocitrate dehydrogenase ( IDH1 or IDH2 , respectively) contribute to oncogenesis via production of... |
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| SubjectTerms | Acute Disease Adenocarcinoma - drug therapy Adenocarcinoma - enzymology Adenocarcinoma - genetics Aged Drug Resistance - genetics Enzyme Inhibitors - pharmacology Female Humans Isocitrate Dehydrogenase - antagonists & inhibitors Isocitrate Dehydrogenase - genetics Isocitrate Dehydrogenase - metabolism Isoenzymes - antagonists & inhibitors Isoenzymes - genetics Isoenzymes - metabolism Leukemia, Myeloid - drug therapy Leukemia, Myeloid - enzymology Leukemia, Myeloid - genetics Liver Neoplasms - drug therapy Liver Neoplasms - enzymology Liver Neoplasms - genetics Male Middle Aged Mutation Myelodysplastic Syndromes - drug therapy Myelodysplastic Syndromes - enzymology Myelodysplastic Syndromes - genetics |
| Title | Isoform Switching as a Mechanism of Acquired Resistance to Mutant Isocitrate Dehydrogenase Inhibition |
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