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

Publication date: 30 May 2017
Source:Cell Reports, Volume 19, Issue 9
Author(s): 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
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.

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Teaser

Calvert et al. demonstrate that wild-type IDH1 is overexpressed in glioblastoma and that genetic or pharmacological suppression of IDH1 activity reduces tumor cell growth through effect on lipid production, redox homeostasis, and the regulation of cellular differentiation.


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