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; Foteini Kouri; Yingtao Bi; Maureen Kachman; Jasmine L. May; Elizabeth Thomas Bartom; Youjia Hua; Rama K Mishra; Gary E Schiltz; Oleksii Dubrovskyi; Andrew P. Mazar; Marcus Ernst Peter; Hongwu Zheng; Charles David James; Charles F. Burant; Navdeep Chandel; Ramana V Davuluri; Craig Michael Horbinski; Alexander H Stegh

doi:10.1016/j.celrep.2017.05.014

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, Foteini Kouri, Yingtao Bi, Maureen Kachman, Jasmine L. May, Elizabeth Thomas Bartom, Youjia Hua, Rama K Mishra, Gary E Schiltz, Oleksii Dubrovskyi, Andrew P. Mazar, Marcus Ernst Peter, Hongwu Zheng, Charles David James, Charles F. Burant, Navdeep Chandel, Ramana V DavuluriCraig Michael Horbinski, Alexander H Stegh^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

162 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1858-1873
Number of pages	16
Journal	Cell reports
Volume	19
Issue number	9
DOIs	https://doi.org/10.1016/j.celrep.2017.05.014
State	Published - May 30 2017

Funding

This research was supported by the Center for Cancer Nanotechnology Excellence (CCNE) initiative of the NIH under award U54 CA199091, by the Alliance for Cancer Gene Therapy (ACGT), the Dixon Translational Research Grants Initiative of the Northwestern Memorial Foundation, and the Coffman Charitable Trust (to A.H.S.). This research was also supported by National Cancer Institute (NCI)/NIH training grant T32CA09560 (to A.E.C.). We would like to thank the Cell Imaging Facility, the Flow Cytometry Core Facility, the Mouse Histology and Phenotyping Laboratory, and the Medicinal and Synthetic Chemistry Core at Northwestern University, all of which are supported by NCI support grant P30 CA060553, awarded to the Robert H. Lurie Comprehensive Cancer Center. The Northwestern Nervous System Tumor Bank provided immunohistochemical analysis of patient-derived gliomas. The Northwestern University Biochemistry and Molecular Genetics Sequencing Core Facility provided next-generation sequencing. The Skin Disease Research Center DNA/RNA Delivery Core helped with virus production. The Metabolomics Core at the University of Michigan, which was supported by grant U24 DK097153 of the NIH Common Funds Project, performed the carbon metabolic labeling studies. The BioTek Instruments Cytation 3 automated imager and plate reader were used in the Analytical BioNanoTechnology Equipment Core of the Simpson Querrey Institute at Northwestern University, which was supported by the U.S. Army Research Office, the U.S. Army Medical Research and Material Command, and Northwestern University.

Keywords

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

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2017.05.014

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Calvert, A. E., Chalastanis, A., Wu, Y., Hurley, L. A., Kouri, F., Bi, Y., Kachman, M., May, J. L., Bartom, E. T., 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., ... Stegh, A. H. (2017). Cancer-Associated IDH1 Promotes Growth and Resistance to Targeted Therapies in the Absence of Mutation. Cell reports, 19(9), 1858-1873. https://doi.org/10.1016/j.celrep.2017.05.014

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

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",

author = "Calvert, {Andrea E.} and Alexandra Chalastanis and Yongfei Wu and Hurley, {Lisa A.} and Foteini Kouri and Yingtao Bi and Maureen Kachman and May, {Jasmine L.} and Bartom, {Elizabeth Thomas} and Youjia Hua and Mishra, {Rama K} and Schiltz, {Gary E} and Oleksii Dubrovskyi and Mazar, {Andrew P.} and Peter, {Marcus Ernst} and Hongwu Zheng and James, {Charles David} and Burant, {Charles F.} and Navdeep Chandel and Davuluri, {Ramana V} and Horbinski, {Craig Michael} and Stegh, {Alexander H}",

note = "Publisher Copyright: {\textcopyright} 2017 The Authors",

year = "2017",

month = may,

day = "30",

doi = "10.1016/j.celrep.2017.05.014",

language = "English (US)",

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Calvert, AE, Chalastanis, A, Wu, Y, Hurley, LA, Kouri, F, Bi, Y, Kachman, M, May, JL, Bartom, ET, Hua, Y, Mishra, RK , Schiltz, GE, Dubrovskyi, O, Mazar, AP, Peter, ME, Zheng, H, James, CD, Burant, CF, Chandel, N, Davuluri, RV, Horbinski, CM & Stegh, AH 2017, 'Cancer-Associated IDH1 Promotes Growth and Resistance to Targeted Therapies in the Absence of Mutation', Cell reports, vol. 19, no. 9, pp. 1858-1873. https://doi.org/10.1016/j.celrep.2017.05.014

TY - JOUR

T1 - Cancer-Associated IDH1 Promotes Growth and Resistance to Targeted Therapies in the Absence of Mutation

AU - Calvert, Andrea E.

AU - Chalastanis, Alexandra

AU - Wu, Yongfei

AU - Hurley, Lisa A.

AU - Kouri, Foteini

AU - Bi, Yingtao

AU - Kachman, Maureen

AU - May, Jasmine L.

AU - Bartom, Elizabeth Thomas

AU - Hua, Youjia

AU - Mishra, Rama K

AU - Schiltz, Gary E

AU - Dubrovskyi, Oleksii

AU - Mazar, Andrew P.

AU - Peter, Marcus Ernst

AU - Zheng, Hongwu

AU - James, Charles David

AU - Burant, Charles F.

AU - Chandel, Navdeep

AU - Davuluri, Ramana V

AU - Horbinski, Craig Michael

AU - Stegh, Alexander H

PY - 2017/5/30

Y1 - 2017/5/30

N2 - 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.

AB - 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.

KW - EGFR

KW - GBM

KW - NADPH

KW - differentiation

KW - lipids

KW - metabolism

KW - reactive oxygen species (ROS)

KW - targeted therapy

KW - wild-type IDH1

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DO - 10.1016/j.celrep.2017.05.014

M3 - Article

C2 - 28564604

AN - SCOPUS:85020009065

SN - 2211-1247

VL - 19

SP - 1858

EP - 1873

JO - Cell reports

JF - Cell reports

IS - 9

ER -

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

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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