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 & 2 others Craig Michael Horbinski, Alexander H Stegh*

*Corresponding author for this work

Research output: Contribution to journalArticle

24 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)1858-1873
Number of pages16
JournalCell reports
Volume19
Issue number9
DOIs
StatePublished - May 30 2017

Fingerprint

Bearings (structural)
Isocitrate Dehydrogenase
Gene encoding
Methylation
Differentiation Antigens
Cell growth
Glioblastoma
NADP
Heterografts
Histones
Glutathione
Tumors
Reactive Oxygen Species
Animals
Acetates
Carbon
Cells
Apoptosis
Fluxes
Lipids

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Calvert, Andrea E. ; Chalastanis, Alexandra ; Wu, Yongfei ; Hurley, Lisa A. ; Kouri, Foteini ; Bi, Yingtao ; Kachman, Maureen ; May, Jasmine L. ; Bartom, Elizabeth Thomas ; Hua, Youjia ; Mishra, Rama K ; Schiltz, Gary E ; Dubrovskyi, Oleksii ; Mazar, Andrew P. ; Peter, Marcus Ernst ; Zheng, Hongwu ; James, Charles David ; Burant, Charles F. ; Chandel, Navdeep ; Davuluri, Ramana V ; Horbinski, Craig Michael ; Stegh, Alexander H. / Cancer-Associated IDH1 Promotes Growth and Resistance to Targeted Therapies in the Absence of Mutation. In: Cell reports. 2017 ; Vol. 19, No. 9. pp. 1858-1873.
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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.",
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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

Cancer-Associated IDH1 Promotes Growth and Resistance to Targeted Therapies in the Absence of Mutation. / Calvert, Andrea E.; Chalastanis, Alexandra; Wu, Yongfei; Hurley, Lisa A.; Kouri, Foteini; Bi, Yingtao; Kachman, Maureen; May, Jasmine L.; Bartom, Elizabeth Thomas; Hua, Youjia; Mishra, Rama K; Schiltz, Gary E; Dubrovskyi, Oleksii; Mazar, Andrew P.; Peter, Marcus Ernst; Zheng, Hongwu; James, Charles David; Burant, Charles F.; Chandel, Navdeep; Davuluri, Ramana V; Horbinski, Craig Michael; Stegh, Alexander H.

In: Cell reports, Vol. 19, No. 9, 30.05.2017, p. 1858-1873.

Research output: Contribution to journalArticle

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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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