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DDRE-08. NRF2/GLUTATHIONE METABOLISM AS A NOVEL THERAPEUTIC TARGET FOR IDH1-MUTATED GLIOMA

BACKGROUND: IDH1-mutated glioma is a recently defined disease entity with distinctive patterns of tumor cell biology, metabolism, and resistance to therapy. Although IDH1 mutations are highly prevalent in patients with WHO II/III glioma, curative molecular targeting approaches remain unavailable for...

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Autores principales: Liu, Yang, Yu, Di, Celiku, Orieta, Li, Aiguo, Larion, Mioara, Yang, Chunzhang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992271/
http://dx.doi.org/10.1093/noajnl/vdab024.030
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author Liu, Yang
Yu, Di
Celiku, Orieta
Li, Aiguo
Larion, Mioara
Yang, Chunzhang
author_facet Liu, Yang
Yu, Di
Celiku, Orieta
Li, Aiguo
Larion, Mioara
Yang, Chunzhang
author_sort Liu, Yang
collection PubMed
description BACKGROUND: IDH1-mutated glioma is a recently defined disease entity with distinctive patterns of tumor cell biology, metabolism, and resistance to therapy. Although IDH1 mutations are highly prevalent in patients with WHO II/III glioma, curative molecular targeting approaches remain unavailable for this disease cluster. METHODS: In the present study, we investigated the glutathione de novo synthesis pathway through the TCGA patient cohort and patient-derived cell lines with IDH1 mutation. The biologic function of nuclear factor erythroid 2-related factor 2 (NRF2) was analyzed by biochemistry and cell biology assays. Finally, NRF2 inhibitors were evaluated in IDH1-mutated cell lines and preclinical models as an experimental therapy. RESULTS: IDH1 mutant neomorphic activity depletes the cellular pools of enzyme cofactors such as nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). The limitation of NAD(P) not only affects the anabolic reactions, but also results in oxidative stress and damages on DNA and protein. Further, we showed that the reprogrammed redox landscape results in constitutive activation of NRF2-governed cytoprotective pathways through the decoupling of NRF2 from its E3 ligase Kelch-like ECH-associated protein 1. NRF2 mediated the transcriptional activation of GCLC, GCLM, and SLC7A11, which not only strengthens the glutathione de novo synthesis, but also relieves the metabolic burden in IDH1-mutated cells. The importance of the glutathione synthesis is further confirmed through COX regression analysis on lower-grade glioma. Blockade of the NRF2/glutathione metabolic pathway synergizes with the elevated intrinsic oxidative stress, which results in overwhelming oxidative damage, as well as a substantial reduction in tumor cell proliferation and xenograft expansion. CONCLUSION: We report that the NRF2-guided cytoprotective pathways play pivotal roles in the disease progression of IDH1-mutated glioma. Targeting NRF2 and glutathione metabolism could be novel targeting strategies for IDH1-mutated glioma.
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spelling pubmed-79922712021-03-31 DDRE-08. NRF2/GLUTATHIONE METABOLISM AS A NOVEL THERAPEUTIC TARGET FOR IDH1-MUTATED GLIOMA Liu, Yang Yu, Di Celiku, Orieta Li, Aiguo Larion, Mioara Yang, Chunzhang Neurooncol Adv Supplement Abstracts BACKGROUND: IDH1-mutated glioma is a recently defined disease entity with distinctive patterns of tumor cell biology, metabolism, and resistance to therapy. Although IDH1 mutations are highly prevalent in patients with WHO II/III glioma, curative molecular targeting approaches remain unavailable for this disease cluster. METHODS: In the present study, we investigated the glutathione de novo synthesis pathway through the TCGA patient cohort and patient-derived cell lines with IDH1 mutation. The biologic function of nuclear factor erythroid 2-related factor 2 (NRF2) was analyzed by biochemistry and cell biology assays. Finally, NRF2 inhibitors were evaluated in IDH1-mutated cell lines and preclinical models as an experimental therapy. RESULTS: IDH1 mutant neomorphic activity depletes the cellular pools of enzyme cofactors such as nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). The limitation of NAD(P) not only affects the anabolic reactions, but also results in oxidative stress and damages on DNA and protein. Further, we showed that the reprogrammed redox landscape results in constitutive activation of NRF2-governed cytoprotective pathways through the decoupling of NRF2 from its E3 ligase Kelch-like ECH-associated protein 1. NRF2 mediated the transcriptional activation of GCLC, GCLM, and SLC7A11, which not only strengthens the glutathione de novo synthesis, but also relieves the metabolic burden in IDH1-mutated cells. The importance of the glutathione synthesis is further confirmed through COX regression analysis on lower-grade glioma. Blockade of the NRF2/glutathione metabolic pathway synergizes with the elevated intrinsic oxidative stress, which results in overwhelming oxidative damage, as well as a substantial reduction in tumor cell proliferation and xenograft expansion. CONCLUSION: We report that the NRF2-guided cytoprotective pathways play pivotal roles in the disease progression of IDH1-mutated glioma. Targeting NRF2 and glutathione metabolism could be novel targeting strategies for IDH1-mutated glioma. Oxford University Press 2021-03-25 /pmc/articles/PMC7992271/ http://dx.doi.org/10.1093/noajnl/vdab024.030 Text en © The Author(s) 2021. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Supplement Abstracts
Liu, Yang
Yu, Di
Celiku, Orieta
Li, Aiguo
Larion, Mioara
Yang, Chunzhang
DDRE-08. NRF2/GLUTATHIONE METABOLISM AS A NOVEL THERAPEUTIC TARGET FOR IDH1-MUTATED GLIOMA
title DDRE-08. NRF2/GLUTATHIONE METABOLISM AS A NOVEL THERAPEUTIC TARGET FOR IDH1-MUTATED GLIOMA
title_full DDRE-08. NRF2/GLUTATHIONE METABOLISM AS A NOVEL THERAPEUTIC TARGET FOR IDH1-MUTATED GLIOMA
title_fullStr DDRE-08. NRF2/GLUTATHIONE METABOLISM AS A NOVEL THERAPEUTIC TARGET FOR IDH1-MUTATED GLIOMA
title_full_unstemmed DDRE-08. NRF2/GLUTATHIONE METABOLISM AS A NOVEL THERAPEUTIC TARGET FOR IDH1-MUTATED GLIOMA
title_short DDRE-08. NRF2/GLUTATHIONE METABOLISM AS A NOVEL THERAPEUTIC TARGET FOR IDH1-MUTATED GLIOMA
title_sort ddre-08. nrf2/glutathione metabolism as a novel therapeutic target for idh1-mutated glioma
topic Supplement Abstracts
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992271/
http://dx.doi.org/10.1093/noajnl/vdab024.030
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