Cargando…
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...
Autores principales: | , , , , , , , |
---|---|
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 |
_version_ | 1783727386459635712 |
---|---|
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. |
format | Online Article Text |
id | pubmed-8304651 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT alconclara erbreastcancerstronglydependsonmcl1andbclxlantiapoptoticproteins AT zanudojorgegomeztejeda erbreastcancerstronglydependsonmcl1andbclxlantiapoptoticproteins AT albertreka erbreastcancerstronglydependsonmcl1andbclxlantiapoptoticproteins AT waglenikhil erbreastcancerstronglydependsonmcl1andbclxlantiapoptoticproteins AT scaltritimaurizio erbreastcancerstronglydependsonmcl1andbclxlantiapoptoticproteins AT letaianthony erbreastcancerstronglydependsonmcl1andbclxlantiapoptoticproteins AT samitierjosep erbreastcancerstronglydependsonmcl1andbclxlantiapoptoticproteins AT monterojoan erbreastcancerstronglydependsonmcl1andbclxlantiapoptoticproteins |