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Resistance to different anthracycline chemotherapeutics elicits distinct and actionable primary metabolic dependencies in breast cancer
Chemotherapy resistance is a critical barrier in cancer treatment. Metabolic adaptations have been shown to fuel therapy resistance; however, little is known regarding the generality of these changes and whether specific therapies elicit unique metabolic alterations. Using a combination of metabolom...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238502/ https://www.ncbi.nlm.nih.gov/pubmed/34181531 http://dx.doi.org/10.7554/eLife.65150 |
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author | McGuirk, Shawn Audet-Delage, Yannick Annis, Matthew G Xue, Yibo Vernier, Mathieu Zhao, Kaiqiong St-Louis, Catherine Minarrieta, Lucía Patten, David A Morin, Geneviève Greenwood, Celia MT Giguère, Vincent Huang, Sidong Siegel, Peter M St-Pierre, Julie |
author_facet | McGuirk, Shawn Audet-Delage, Yannick Annis, Matthew G Xue, Yibo Vernier, Mathieu Zhao, Kaiqiong St-Louis, Catherine Minarrieta, Lucía Patten, David A Morin, Geneviève Greenwood, Celia MT Giguère, Vincent Huang, Sidong Siegel, Peter M St-Pierre, Julie |
author_sort | McGuirk, Shawn |
collection | PubMed |
description | Chemotherapy resistance is a critical barrier in cancer treatment. Metabolic adaptations have been shown to fuel therapy resistance; however, little is known regarding the generality of these changes and whether specific therapies elicit unique metabolic alterations. Using a combination of metabolomics, transcriptomics, and functional genomics, we show that two anthracyclines, doxorubicin and epirubicin, elicit distinct primary metabolic vulnerabilities in human breast cancer cells. Doxorubicin-resistant cells rely on glutamine to drive oxidative phosphorylation and de novo glutathione synthesis, while epirubicin-resistant cells display markedly increased bioenergetic capacity and mitochondrial ATP production. The dependence on these distinct metabolic adaptations is revealed by the increased sensitivity of doxorubicin-resistant cells and tumor xenografts to buthionine sulfoximine (BSO), a drug that interferes with glutathione synthesis, compared with epirubicin-resistant counterparts that are more sensitive to the biguanide phenformin. Overall, our work reveals that metabolic adaptations can vary with therapeutics and that these metabolic dependencies can be exploited as a targeted approach to treat chemotherapy-resistant breast cancer. |
format | Online Article Text |
id | pubmed-8238502 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-82385022021-06-30 Resistance to different anthracycline chemotherapeutics elicits distinct and actionable primary metabolic dependencies in breast cancer McGuirk, Shawn Audet-Delage, Yannick Annis, Matthew G Xue, Yibo Vernier, Mathieu Zhao, Kaiqiong St-Louis, Catherine Minarrieta, Lucía Patten, David A Morin, Geneviève Greenwood, Celia MT Giguère, Vincent Huang, Sidong Siegel, Peter M St-Pierre, Julie eLife Cancer Biology Chemotherapy resistance is a critical barrier in cancer treatment. Metabolic adaptations have been shown to fuel therapy resistance; however, little is known regarding the generality of these changes and whether specific therapies elicit unique metabolic alterations. Using a combination of metabolomics, transcriptomics, and functional genomics, we show that two anthracyclines, doxorubicin and epirubicin, elicit distinct primary metabolic vulnerabilities in human breast cancer cells. Doxorubicin-resistant cells rely on glutamine to drive oxidative phosphorylation and de novo glutathione synthesis, while epirubicin-resistant cells display markedly increased bioenergetic capacity and mitochondrial ATP production. The dependence on these distinct metabolic adaptations is revealed by the increased sensitivity of doxorubicin-resistant cells and tumor xenografts to buthionine sulfoximine (BSO), a drug that interferes with glutathione synthesis, compared with epirubicin-resistant counterparts that are more sensitive to the biguanide phenformin. Overall, our work reveals that metabolic adaptations can vary with therapeutics and that these metabolic dependencies can be exploited as a targeted approach to treat chemotherapy-resistant breast cancer. eLife Sciences Publications, Ltd 2021-06-28 /pmc/articles/PMC8238502/ /pubmed/34181531 http://dx.doi.org/10.7554/eLife.65150 Text en © 2021, McGuirk et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Cancer Biology McGuirk, Shawn Audet-Delage, Yannick Annis, Matthew G Xue, Yibo Vernier, Mathieu Zhao, Kaiqiong St-Louis, Catherine Minarrieta, Lucía Patten, David A Morin, Geneviève Greenwood, Celia MT Giguère, Vincent Huang, Sidong Siegel, Peter M St-Pierre, Julie Resistance to different anthracycline chemotherapeutics elicits distinct and actionable primary metabolic dependencies in breast cancer |
title | Resistance to different anthracycline chemotherapeutics elicits distinct and actionable primary metabolic dependencies in breast cancer |
title_full | Resistance to different anthracycline chemotherapeutics elicits distinct and actionable primary metabolic dependencies in breast cancer |
title_fullStr | Resistance to different anthracycline chemotherapeutics elicits distinct and actionable primary metabolic dependencies in breast cancer |
title_full_unstemmed | Resistance to different anthracycline chemotherapeutics elicits distinct and actionable primary metabolic dependencies in breast cancer |
title_short | Resistance to different anthracycline chemotherapeutics elicits distinct and actionable primary metabolic dependencies in breast cancer |
title_sort | resistance to different anthracycline chemotherapeutics elicits distinct and actionable primary metabolic dependencies in breast cancer |
topic | Cancer Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238502/ https://www.ncbi.nlm.nih.gov/pubmed/34181531 http://dx.doi.org/10.7554/eLife.65150 |
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