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

Calvert, A. E., Chalastanis, A., Wu, Y., Hurley, L. A., Kouri, F. M., Bi, Y., Kachman, M., May, J. L., Bartom, E., Hua, Y., Mishra, R. K., Schiltz, G. E., Dubrovskyi, O., Mazar, A. P., Peter, M. E., Zheng, H., James, C. D., Burant, C. F., Chandel, N. S., Davuluri, R. V., Horbinski, C., Stegh, A. H. (2017) Cancer-Associated IDH1 Promotes Growth and Resistance to Targeted Therapies in the Absence of Mutation. Cell Rep, 19 (9). pp. 1858-1873.

URL: https://www.ncbi.nlm.nih.gov/pubmed/28564604
DOI: 10.1016/j.celrep.2017.05.014

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 alpha-ketoglutarate (alphaKG) 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.

Item Type: Paper
Uncontrolled Keywords: Egfr Gbm Nadph differentiation lipids metabolism reactive oxygen species (ROS) targeted therapy wild-type IDH1
Subjects: diseases & disorders > cancer > cancer types > glioblastoma
organs, tissues, organelles, cell types and functions > organs types and functions > metabolism
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > mutations
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > oncogene
diseases & disorders > pulmonary disease > oxidative stress
CSHL Authors:
Communities: CSHL labs > Zheng lab
CSHL Cancer Center Program > Signal Transduction
Depositing User: Matt Covey
Date Deposited: 12 Jun 2017 19:46
Last Modified: 13 Jun 2018 15:47
PMCID: PMC5564207
Related URLs:
URI: http://repository.cshl.edu/id/eprint/34920

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