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ER+ Breast Cancer Strongly Depends on MCL-1 and BCL-xL Anti-Apoptotic Proteins

Breast cancer is the most frequent type of cancer and the major cause of mortality in women. The rapid development of various therapeutic options has led to the improvement of treatment outcomes; nevertheless, one-third of estrogen receptor (ER)-positive patients relapse due to cancer cell acquired...

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Autores principales: Alcon, Clara, Zañudo, Jorge Gómez Tejeda, Albert, Reka, Wagle, Nikhil, Scaltriti, Maurizio, Letai, Anthony, Samitier, Josep, Montero, Joan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8304651/
https://www.ncbi.nlm.nih.gov/pubmed/34359829
http://dx.doi.org/10.3390/cells10071659
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author Alcon, Clara
Zañudo, Jorge Gómez Tejeda
Albert, Reka
Wagle, Nikhil
Scaltriti, Maurizio
Letai, Anthony
Samitier, Josep
Montero, Joan
author_facet Alcon, Clara
Zañudo, Jorge Gómez Tejeda
Albert, Reka
Wagle, Nikhil
Scaltriti, Maurizio
Letai, Anthony
Samitier, Josep
Montero, Joan
author_sort Alcon, Clara
collection PubMed
description Breast cancer is the most frequent type of cancer and the major cause of mortality in women. The rapid development of various therapeutic options has led to the improvement of treatment outcomes; nevertheless, one-third of estrogen receptor (ER)-positive patients relapse due to cancer cell acquired resistance. Here, we use dynamic BH3 profiling (DBP), a functional predictive assay that measures net changes in apoptotic priming, to find new effective treatments for ER+ breast cancer. We observed anti-apoptotic adaptations upon treatment that pointed to metronomic therapeutic combinations to enhance cytotoxicity and avoid resistance. Indeed, we found that the anti-apoptotic proteins BCL-xL and MCL-1 are crucial for ER+ breast cancer cells resistance to therapy, as they exert a dual inhibition of the pro-apoptotic protein BIM and compensate for each other. In addition, we identified the AKT inhibitor ipatasertib and two BH3 mimetics targeting these anti-apoptotic proteins, S63845 and A-1331852, as new potential therapies for this type of cancer. Therefore, we postulate the sequential inhibition of both proteins using BH3 mimetics as a new treatment option for refractory and relapsed ER+ breast cancer tumors.
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spelling pubmed-83046512021-07-25 ER+ Breast Cancer Strongly Depends on MCL-1 and BCL-xL Anti-Apoptotic Proteins Alcon, Clara Zañudo, Jorge Gómez Tejeda Albert, Reka Wagle, Nikhil Scaltriti, Maurizio Letai, Anthony Samitier, Josep Montero, Joan Cells Article Breast cancer is the most frequent type of cancer and the major cause of mortality in women. The rapid development of various therapeutic options has led to the improvement of treatment outcomes; nevertheless, one-third of estrogen receptor (ER)-positive patients relapse due to cancer cell acquired resistance. Here, we use dynamic BH3 profiling (DBP), a functional predictive assay that measures net changes in apoptotic priming, to find new effective treatments for ER+ breast cancer. We observed anti-apoptotic adaptations upon treatment that pointed to metronomic therapeutic combinations to enhance cytotoxicity and avoid resistance. Indeed, we found that the anti-apoptotic proteins BCL-xL and MCL-1 are crucial for ER+ breast cancer cells resistance to therapy, as they exert a dual inhibition of the pro-apoptotic protein BIM and compensate for each other. In addition, we identified the AKT inhibitor ipatasertib and two BH3 mimetics targeting these anti-apoptotic proteins, S63845 and A-1331852, as new potential therapies for this type of cancer. Therefore, we postulate the sequential inhibition of both proteins using BH3 mimetics as a new treatment option for refractory and relapsed ER+ breast cancer tumors. MDPI 2021-07-02 /pmc/articles/PMC8304651/ /pubmed/34359829 http://dx.doi.org/10.3390/cells10071659 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Alcon, Clara
Zañudo, Jorge Gómez Tejeda
Albert, Reka
Wagle, Nikhil
Scaltriti, Maurizio
Letai, Anthony
Samitier, Josep
Montero, Joan
ER+ Breast Cancer Strongly Depends on MCL-1 and BCL-xL Anti-Apoptotic Proteins
title ER+ Breast Cancer Strongly Depends on MCL-1 and BCL-xL Anti-Apoptotic Proteins
title_full ER+ Breast Cancer Strongly Depends on MCL-1 and BCL-xL Anti-Apoptotic Proteins
title_fullStr ER+ Breast Cancer Strongly Depends on MCL-1 and BCL-xL Anti-Apoptotic Proteins
title_full_unstemmed ER+ Breast Cancer Strongly Depends on MCL-1 and BCL-xL Anti-Apoptotic Proteins
title_short ER+ Breast Cancer Strongly Depends on MCL-1 and BCL-xL Anti-Apoptotic Proteins
title_sort er+ breast cancer strongly depends on mcl-1 and bcl-xl anti-apoptotic proteins
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8304651/
https://www.ncbi.nlm.nih.gov/pubmed/34359829
http://dx.doi.org/10.3390/cells10071659
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