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Pak1 pathway hyper-activation mediates resistance to endocrine therapy and CDK4/6 inhibitors in ER+ breast cancer

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) have been approved in combination with endocrine therapy (ET) to treat estrogen receptor-positive (ER+) metastatic breast cancer (BC). However, drug resistance represents the leading cause of breast cancer patients mortality. This study aimed to i...

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Autores principales: Belli, Stefania, Esposito, Daniela, Allotta, Alessandra, Servetto, Alberto, Ciciola, Paola, Pesapane, Ada, Ascione, Claudia M., Napolitano, Fabiana, Di Mauro, Concetta, Vigliar, Elena, Iaccarino, Antonino, De Angelis, Carmine, Bianco, Roberto, Formisano, Luigi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10232479/
https://www.ncbi.nlm.nih.gov/pubmed/37258566
http://dx.doi.org/10.1038/s41523-023-00556-9
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author Belli, Stefania
Esposito, Daniela
Allotta, Alessandra
Servetto, Alberto
Ciciola, Paola
Pesapane, Ada
Ascione, Claudia M.
Napolitano, Fabiana
Di Mauro, Concetta
Vigliar, Elena
Iaccarino, Antonino
De Angelis, Carmine
Bianco, Roberto
Formisano, Luigi
author_facet Belli, Stefania
Esposito, Daniela
Allotta, Alessandra
Servetto, Alberto
Ciciola, Paola
Pesapane, Ada
Ascione, Claudia M.
Napolitano, Fabiana
Di Mauro, Concetta
Vigliar, Elena
Iaccarino, Antonino
De Angelis, Carmine
Bianco, Roberto
Formisano, Luigi
author_sort Belli, Stefania
collection PubMed
description Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) have been approved in combination with endocrine therapy (ET) to treat estrogen receptor-positive (ER+) metastatic breast cancer (BC). However, drug resistance represents the leading cause of breast cancer patients mortality. This study aimed to identify novel resistance mechanisms to ER antagonists in combination with CDK4/6 inhibitors. We generated two ER+ BC cell lines, T47D and MCF7, resistant to the combination of the ER antagonist fulvestrant and CDK4/6i abemaciclib, named T47D-FAR and MCF7-FAR. Transcriptomic analysis revealed common up-regulation of genes involved in MAPK and epithelial to mesenchymal transition (EMT) pathways in FAR cells, sustaining their hyper-invasive phenotype and increased anchorage-independent growth, compared to sensitive cells. FAR cells showed higher p21-activated kinase 1 (Pak1) expression and phosphorylation levels than parental cells. PAK1 knockdown by siRNAs hampered cell proliferation, reduced anchorage-independent growth and invasive properties of T47D-FAR and MCF7-FAR, re-sensitizing them to fulvestrant and abemaciclib. Conversely, over-expression of PAK1 in MCF7 and T47D cells increased tumor spheroids’ growth and invasion and reduced sensitivity to fulvestrant and abemaciclib, confirming its role in inducing drug resistance. Finally, treatment with Pak1 inhibitors, PF-3758309 (PF309) and NVS-PAK1-1, restored cell sensitivity to fulvestrant and abemaciclib of MCF7-FAR and T47D-FAR cells, both in vitro and in vivo. In conclusion, our data suggested a pivotal role for Pak1 in resistance to ET and CDK4/6i in ER+ breast cancers. These data might promote the rationale for the development of novel Pak1 inhibitors for treatment of patients with ER+ BC progressing on ET plus CDK4/6i.
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spelling pubmed-102324792023-06-02 Pak1 pathway hyper-activation mediates resistance to endocrine therapy and CDK4/6 inhibitors in ER+ breast cancer Belli, Stefania Esposito, Daniela Allotta, Alessandra Servetto, Alberto Ciciola, Paola Pesapane, Ada Ascione, Claudia M. Napolitano, Fabiana Di Mauro, Concetta Vigliar, Elena Iaccarino, Antonino De Angelis, Carmine Bianco, Roberto Formisano, Luigi NPJ Breast Cancer Article Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) have been approved in combination with endocrine therapy (ET) to treat estrogen receptor-positive (ER+) metastatic breast cancer (BC). However, drug resistance represents the leading cause of breast cancer patients mortality. This study aimed to identify novel resistance mechanisms to ER antagonists in combination with CDK4/6 inhibitors. We generated two ER+ BC cell lines, T47D and MCF7, resistant to the combination of the ER antagonist fulvestrant and CDK4/6i abemaciclib, named T47D-FAR and MCF7-FAR. Transcriptomic analysis revealed common up-regulation of genes involved in MAPK and epithelial to mesenchymal transition (EMT) pathways in FAR cells, sustaining their hyper-invasive phenotype and increased anchorage-independent growth, compared to sensitive cells. FAR cells showed higher p21-activated kinase 1 (Pak1) expression and phosphorylation levels than parental cells. PAK1 knockdown by siRNAs hampered cell proliferation, reduced anchorage-independent growth and invasive properties of T47D-FAR and MCF7-FAR, re-sensitizing them to fulvestrant and abemaciclib. Conversely, over-expression of PAK1 in MCF7 and T47D cells increased tumor spheroids’ growth and invasion and reduced sensitivity to fulvestrant and abemaciclib, confirming its role in inducing drug resistance. Finally, treatment with Pak1 inhibitors, PF-3758309 (PF309) and NVS-PAK1-1, restored cell sensitivity to fulvestrant and abemaciclib of MCF7-FAR and T47D-FAR cells, both in vitro and in vivo. In conclusion, our data suggested a pivotal role for Pak1 in resistance to ET and CDK4/6i in ER+ breast cancers. These data might promote the rationale for the development of novel Pak1 inhibitors for treatment of patients with ER+ BC progressing on ET plus CDK4/6i. Nature Publishing Group UK 2023-05-31 /pmc/articles/PMC10232479/ /pubmed/37258566 http://dx.doi.org/10.1038/s41523-023-00556-9 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Belli, Stefania
Esposito, Daniela
Allotta, Alessandra
Servetto, Alberto
Ciciola, Paola
Pesapane, Ada
Ascione, Claudia M.
Napolitano, Fabiana
Di Mauro, Concetta
Vigliar, Elena
Iaccarino, Antonino
De Angelis, Carmine
Bianco, Roberto
Formisano, Luigi
Pak1 pathway hyper-activation mediates resistance to endocrine therapy and CDK4/6 inhibitors in ER+ breast cancer
title Pak1 pathway hyper-activation mediates resistance to endocrine therapy and CDK4/6 inhibitors in ER+ breast cancer
title_full Pak1 pathway hyper-activation mediates resistance to endocrine therapy and CDK4/6 inhibitors in ER+ breast cancer
title_fullStr Pak1 pathway hyper-activation mediates resistance to endocrine therapy and CDK4/6 inhibitors in ER+ breast cancer
title_full_unstemmed Pak1 pathway hyper-activation mediates resistance to endocrine therapy and CDK4/6 inhibitors in ER+ breast cancer
title_short Pak1 pathway hyper-activation mediates resistance to endocrine therapy and CDK4/6 inhibitors in ER+ breast cancer
title_sort pak1 pathway hyper-activation mediates resistance to endocrine therapy and cdk4/6 inhibitors in er+ breast cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10232479/
https://www.ncbi.nlm.nih.gov/pubmed/37258566
http://dx.doi.org/10.1038/s41523-023-00556-9
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