Cell Reports (May 2017)
Cancer-Associated IDH1 Promotes Growth and Resistance to Targeted Therapies in the Absence of Mutation
- Andrea E. Calvert,
- Alexandra Chalastanis,
- Yongfei Wu,
- Lisa A. Hurley,
- Fotini M. Kouri,
- Yingtao Bi,
- Maureen Kachman,
- Jasmine L. May,
- Elizabeth Bartom,
- Youjia Hua,
- Rama K. Mishra,
- Gary E. Schiltz,
- Oleksii Dubrovskyi,
- Andrew P. Mazar,
- Marcus E. Peter,
- Hongwu Zheng,
- C. David James,
- Charles F. Burant,
- Navdeep S. Chandel,
- Ramana V. Davuluri,
- Craig Horbinski,
- Alexander H. Stegh
Affiliations
- Andrea E. Calvert
- Ken and Ruth Davee Department of Neurology, The Northwestern Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, International Institute for Nanotechnology, Northwestern University, Chicago, IL 60611, USA
- Alexandra Chalastanis
- Ken and Ruth Davee Department of Neurology, The Northwestern Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, International Institute for Nanotechnology, Northwestern University, Chicago, IL 60611, USA
- Yongfei Wu
- Ken and Ruth Davee Department of Neurology, The Northwestern Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, International Institute for Nanotechnology, Northwestern University, Chicago, IL 60611, USA
- Lisa A. Hurley
- Ken and Ruth Davee Department of Neurology, The Northwestern Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, International Institute for Nanotechnology, Northwestern University, Chicago, IL 60611, USA
- Fotini M. Kouri
- Ken and Ruth Davee Department of Neurology, The Northwestern Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, International Institute for Nanotechnology, Northwestern University, Chicago, IL 60611, USA
- Yingtao Bi
- Division of Health and Biomedical Informatics, Department of Preventive Medicine, The Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
- Maureen Kachman
- Michigan Regional Comprehensive Metabolomics Resource Core, University of Michigan, Ann Arbor, MI 48105, USA
- Jasmine L. May
- Ken and Ruth Davee Department of Neurology, The Northwestern Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, International Institute for Nanotechnology, Northwestern University, Chicago, IL 60611, USA
- Elizabeth Bartom
- Department of Biochemistry and Molecular Genetics, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
- Youjia Hua
- Division of Hematology/Oncology, The Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
- Rama K. Mishra
- Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, IL 60208, USA
- Gary E. Schiltz
- Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, IL 60208, USA
- Oleksii Dubrovskyi
- Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, USA
- Andrew P. Mazar
- Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, USA
- Marcus E. Peter
- Division of Hematology/Oncology, The Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
- Hongwu Zheng
- Cold Spring Harbor Laboratories, Cold Spring Harbor, NY 11724, USA
- C. David James
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
- Charles F. Burant
- Michigan Regional Comprehensive Metabolomics Resource Core, University of Michigan, Ann Arbor, MI 48105, USA
- Navdeep S. Chandel
- Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60615, USA
- Ramana V. Davuluri
- Division of Health and Biomedical Informatics, Department of Preventive Medicine, The Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
- Craig Horbinski
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
- Alexander H. Stegh
- Ken and Ruth Davee Department of Neurology, The Northwestern Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, International Institute for Nanotechnology, Northwestern University, Chicago, IL 60611, USA
- DOI
- https://doi.org/10.1016/j.celrep.2017.05.014
- Journal volume & issue
-
Vol. 19,
no. 9
pp. 1858 – 1873
Abstract
Oncogenic mutations in two isocitrate dehydrogenase (IDH)-encoding genes (IDH1 and IDH2) have been identified in acute myelogenous leukemia, low-grade glioma, and secondary glioblastoma (GBM). Our in silico and wet-bench analyses indicate that non-mutated IDH1 mRNA and protein are commonly overexpressed in primary GBMs. We show that genetic and pharmacologic inactivation of IDH1 decreases GBM cell growth, promotes a more differentiated tumor cell state, increases apoptosis in response to targeted therapies, and prolongs the survival of animal subjects bearing patient-derived xenografts (PDXs). On a molecular level, diminished IDH1 activity results in reduced α-ketoglutarate (αKG) and NADPH production, paralleled by deficient carbon flux from glucose or acetate into lipids, exhaustion of reduced glutathione, increased levels of reactive oxygen species (ROS), and enhanced histone methylation and differentiation marker expression. These findings suggest that IDH1 upregulation represents a common metabolic adaptation by GBMs to support macromolecular synthesis, aggressive growth, and therapy resistance.
Keywords
- wild-type IDH1
- GBM
- metabolism
- differentiation
- NADPH
- lipids
- reactive oxygen species (ROS)
- EGFR
- targeted therapy
