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An integrated stress response via PKR suppresses HER2+ cancers and improves trastuzumab therapy

Trastuzumab is integral to HER2+ cancer treatment, but its therapeutic index is narrowed by the development of resistance. Phosphorylation of the translation initiation factor eIF2α (eIF2α-P) is the nodal point of the integrated stress response, which promotes survival or death in a context-dependen...

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Autores principales: Darini, Cedric, Ghaddar, Nour, Chabot, Catherine, Assaker, Gloria, Sabri, Siham, Wang, Shuo, Krishnamoorthy, Jothilatha, Buchanan, Marguerite, Aguilar-Mahecha, Adriana, Abdulkarim, Bassam, Deschenes, Jean, Torres, Jose, Ursini-Siegel, Josie, Basik, Mark, Koromilas, Antonis E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6513990/
https://www.ncbi.nlm.nih.gov/pubmed/31086176
http://dx.doi.org/10.1038/s41467-019-10138-8
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author Darini, Cedric
Ghaddar, Nour
Chabot, Catherine
Assaker, Gloria
Sabri, Siham
Wang, Shuo
Krishnamoorthy, Jothilatha
Buchanan, Marguerite
Aguilar-Mahecha, Adriana
Abdulkarim, Bassam
Deschenes, Jean
Torres, Jose
Ursini-Siegel, Josie
Basik, Mark
Koromilas, Antonis E.
author_facet Darini, Cedric
Ghaddar, Nour
Chabot, Catherine
Assaker, Gloria
Sabri, Siham
Wang, Shuo
Krishnamoorthy, Jothilatha
Buchanan, Marguerite
Aguilar-Mahecha, Adriana
Abdulkarim, Bassam
Deschenes, Jean
Torres, Jose
Ursini-Siegel, Josie
Basik, Mark
Koromilas, Antonis E.
author_sort Darini, Cedric
collection PubMed
description Trastuzumab is integral to HER2+ cancer treatment, but its therapeutic index is narrowed by the development of resistance. Phosphorylation of the translation initiation factor eIF2α (eIF2α-P) is the nodal point of the integrated stress response, which promotes survival or death in a context-dependent manner. Here, we show an anti-tumor function of the protein kinase PKR and its substrate eIF2α in a mouse HER2+ breast cancer model. The anti-tumor function depends on the transcription factor ATF4, which upregulates the CDK inhibitor P21(CIP1) and activates JNK1/2. The PKR/eIF2α-P arm is induced by Trastuzumab in sensitive but not resistant HER2+ breast tumors. Also, eIF2α-P stimulation by the phosphatase inhibitor SAL003 substantially increases Trastuzumab potency in resistant HER2+ breast and gastric tumors. Increased eIF2α-P prognosticates a better response of HER2+ metastatic breast cancer patients to Trastuzumab therapy. Hence, the PKR/eIF2α-P arm antagonizes HER2 tumorigenesis whereas its pharmacological stimulation improves the efficacy of Trastuzumab therapy.
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spelling pubmed-65139902019-05-15 An integrated stress response via PKR suppresses HER2+ cancers and improves trastuzumab therapy Darini, Cedric Ghaddar, Nour Chabot, Catherine Assaker, Gloria Sabri, Siham Wang, Shuo Krishnamoorthy, Jothilatha Buchanan, Marguerite Aguilar-Mahecha, Adriana Abdulkarim, Bassam Deschenes, Jean Torres, Jose Ursini-Siegel, Josie Basik, Mark Koromilas, Antonis E. Nat Commun Article Trastuzumab is integral to HER2+ cancer treatment, but its therapeutic index is narrowed by the development of resistance. Phosphorylation of the translation initiation factor eIF2α (eIF2α-P) is the nodal point of the integrated stress response, which promotes survival or death in a context-dependent manner. Here, we show an anti-tumor function of the protein kinase PKR and its substrate eIF2α in a mouse HER2+ breast cancer model. The anti-tumor function depends on the transcription factor ATF4, which upregulates the CDK inhibitor P21(CIP1) and activates JNK1/2. The PKR/eIF2α-P arm is induced by Trastuzumab in sensitive but not resistant HER2+ breast tumors. Also, eIF2α-P stimulation by the phosphatase inhibitor SAL003 substantially increases Trastuzumab potency in resistant HER2+ breast and gastric tumors. Increased eIF2α-P prognosticates a better response of HER2+ metastatic breast cancer patients to Trastuzumab therapy. Hence, the PKR/eIF2α-P arm antagonizes HER2 tumorigenesis whereas its pharmacological stimulation improves the efficacy of Trastuzumab therapy. Nature Publishing Group UK 2019-05-13 /pmc/articles/PMC6513990/ /pubmed/31086176 http://dx.doi.org/10.1038/s41467-019-10138-8 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Darini, Cedric
Ghaddar, Nour
Chabot, Catherine
Assaker, Gloria
Sabri, Siham
Wang, Shuo
Krishnamoorthy, Jothilatha
Buchanan, Marguerite
Aguilar-Mahecha, Adriana
Abdulkarim, Bassam
Deschenes, Jean
Torres, Jose
Ursini-Siegel, Josie
Basik, Mark
Koromilas, Antonis E.
An integrated stress response via PKR suppresses HER2+ cancers and improves trastuzumab therapy
title An integrated stress response via PKR suppresses HER2+ cancers and improves trastuzumab therapy
title_full An integrated stress response via PKR suppresses HER2+ cancers and improves trastuzumab therapy
title_fullStr An integrated stress response via PKR suppresses HER2+ cancers and improves trastuzumab therapy
title_full_unstemmed An integrated stress response via PKR suppresses HER2+ cancers and improves trastuzumab therapy
title_short An integrated stress response via PKR suppresses HER2+ cancers and improves trastuzumab therapy
title_sort integrated stress response via pkr suppresses her2+ cancers and improves trastuzumab therapy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6513990/
https://www.ncbi.nlm.nih.gov/pubmed/31086176
http://dx.doi.org/10.1038/s41467-019-10138-8
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