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Cell Rep. 2017 May 30;19(9):1858-1873. doi: 10.1016/j.celrep.2017.05.014.

Cancer-Associated IDH1 Promotes Growth and Resistance to Targeted Therapies in the Absence of Mutation.

Author information

1
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.
2
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.
3
Michigan Regional Comprehensive Metabolomics Resource Core, University of Michigan, Ann Arbor, MI 48105, USA.
4
Department of Biochemistry and Molecular Genetics, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
5
Division of Hematology/Oncology, The Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
6
Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, IL 60208, USA.
7
Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, IL 60208, USA; Department of Pharmacology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611, USA.
8
Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, USA.
9
Cold Spring Harbor Laboratories, Cold Spring Harbor, NY 11724, USA.
10
Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
11
Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60615, USA.
12
Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60615, USA.
13
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. Electronic address: a-stegh@northwestern.edu.

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:

EGFR; GBM; NADPH; differentiation; lipids; metabolism; reactive oxygen species (ROS); targeted therapy; wild-type IDH1

PMID:
28564604
PMCID:
PMC5564207
DOI:
10.1016/j.celrep.2017.05.014
[Indexed for MEDLINE]
Free PMC Article

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