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ERRα mediates metabolic adaptations driving lapatinib resistance in breast cancer

Despite the initial benefits of treating HER2-amplified breast cancer patients with the tyrosine kinase inhibitor lapatinib, resistance inevitably develops. Here we report that lapatinib induces the degradation of the nuclear receptor ERRα, a master regulator of cellular metabolism, and that the exp...

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Autores principales: Deblois, Geneviève, Smith, Harvey W., Tam, Ingrid S., Gravel, Simon-Pierre, Caron, Maxime, Savage, Paul, Labbé, David P., Bégin, Louis R., Tremblay, Michel L., Park, Morag, Bourque, Guillaume, St-Pierre, Julie, Muller, William J., Giguère, Vincent
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4945959/
https://www.ncbi.nlm.nih.gov/pubmed/27402251
http://dx.doi.org/10.1038/ncomms12156
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author Deblois, Geneviève
Smith, Harvey W.
Tam, Ingrid S.
Gravel, Simon-Pierre
Caron, Maxime
Savage, Paul
Labbé, David P.
Bégin, Louis R.
Tremblay, Michel L.
Park, Morag
Bourque, Guillaume
St-Pierre, Julie
Muller, William J.
Giguère, Vincent
author_facet Deblois, Geneviève
Smith, Harvey W.
Tam, Ingrid S.
Gravel, Simon-Pierre
Caron, Maxime
Savage, Paul
Labbé, David P.
Bégin, Louis R.
Tremblay, Michel L.
Park, Morag
Bourque, Guillaume
St-Pierre, Julie
Muller, William J.
Giguère, Vincent
author_sort Deblois, Geneviève
collection PubMed
description Despite the initial benefits of treating HER2-amplified breast cancer patients with the tyrosine kinase inhibitor lapatinib, resistance inevitably develops. Here we report that lapatinib induces the degradation of the nuclear receptor ERRα, a master regulator of cellular metabolism, and that the expression of ERRα is restored in lapatinib-resistant breast cancer cells through reactivation of mTOR signalling. Re-expression of ERRα in resistant cells triggers metabolic adaptations favouring mitochondrial energy metabolism through increased glutamine metabolism, as well as ROS detoxification required for cell survival under therapeutic stress conditions. An ERRα inverse agonist counteracts these metabolic adaptations and overcomes lapatinib resistance in a HER2-induced mammary tumour mouse model. This work reveals a molecular mechanism by which ERRα-induced metabolic reprogramming promotes survival of lapatinib-resistant cancer cells and demonstrates the potential of ERRα inhibition as an effective adjuvant therapy in poor outcome HER2-positive breast cancer.
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spelling pubmed-49459592016-09-06 ERRα mediates metabolic adaptations driving lapatinib resistance in breast cancer Deblois, Geneviève Smith, Harvey W. Tam, Ingrid S. Gravel, Simon-Pierre Caron, Maxime Savage, Paul Labbé, David P. Bégin, Louis R. Tremblay, Michel L. Park, Morag Bourque, Guillaume St-Pierre, Julie Muller, William J. Giguère, Vincent Nat Commun Article Despite the initial benefits of treating HER2-amplified breast cancer patients with the tyrosine kinase inhibitor lapatinib, resistance inevitably develops. Here we report that lapatinib induces the degradation of the nuclear receptor ERRα, a master regulator of cellular metabolism, and that the expression of ERRα is restored in lapatinib-resistant breast cancer cells through reactivation of mTOR signalling. Re-expression of ERRα in resistant cells triggers metabolic adaptations favouring mitochondrial energy metabolism through increased glutamine metabolism, as well as ROS detoxification required for cell survival under therapeutic stress conditions. An ERRα inverse agonist counteracts these metabolic adaptations and overcomes lapatinib resistance in a HER2-induced mammary tumour mouse model. This work reveals a molecular mechanism by which ERRα-induced metabolic reprogramming promotes survival of lapatinib-resistant cancer cells and demonstrates the potential of ERRα inhibition as an effective adjuvant therapy in poor outcome HER2-positive breast cancer. Nature Publishing Group 2016-07-12 /pmc/articles/PMC4945959/ /pubmed/27402251 http://dx.doi.org/10.1038/ncomms12156 Text en Copyright © 2016, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Deblois, Geneviève
Smith, Harvey W.
Tam, Ingrid S.
Gravel, Simon-Pierre
Caron, Maxime
Savage, Paul
Labbé, David P.
Bégin, Louis R.
Tremblay, Michel L.
Park, Morag
Bourque, Guillaume
St-Pierre, Julie
Muller, William J.
Giguère, Vincent
ERRα mediates metabolic adaptations driving lapatinib resistance in breast cancer
title ERRα mediates metabolic adaptations driving lapatinib resistance in breast cancer
title_full ERRα mediates metabolic adaptations driving lapatinib resistance in breast cancer
title_fullStr ERRα mediates metabolic adaptations driving lapatinib resistance in breast cancer
title_full_unstemmed ERRα mediates metabolic adaptations driving lapatinib resistance in breast cancer
title_short ERRα mediates metabolic adaptations driving lapatinib resistance in breast cancer
title_sort errα mediates metabolic adaptations driving lapatinib resistance in breast cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4945959/
https://www.ncbi.nlm.nih.gov/pubmed/27402251
http://dx.doi.org/10.1038/ncomms12156
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