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The Predictive and Prognostic Role of RAS–RAF–MEK–ERK Pathway Alterations in Breast Cancer: Revision of the Literature and Comparison with the Analysis of Cancer Genomic Datasets
SIMPLE SUMMARY: The RAS/RAF/MEK/ERK pathway is implicated in fundamental processes frequently altered in tumors, such as cell proliferation and survival. In breast cancer, it is rarely affected by genomic alterations, but it is activated by membrane receptors or by epigenetic phenomena or readjustme...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9653766/ https://www.ncbi.nlm.nih.gov/pubmed/36358725 http://dx.doi.org/10.3390/cancers14215306 |
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author | Rocca, Andrea Braga, Luca Volpe, Maria Concetta Maiocchi, Serena Generali, Daniele |
author_facet | Rocca, Andrea Braga, Luca Volpe, Maria Concetta Maiocchi, Serena Generali, Daniele |
author_sort | Rocca, Andrea |
collection | PubMed |
description | SIMPLE SUMMARY: The RAS/RAF/MEK/ERK pathway is implicated in fundamental processes frequently altered in tumors, such as cell proliferation and survival. In breast cancer, it is rarely affected by genomic alterations, but it is activated by membrane receptors or by epigenetic phenomena or readjustments in intracellular signaling networks. To date, drugs targeting molecules involved in this pathway have not been effective in the treatment of breast cancer: although successful in in vitro experiments, they fail in clinical trials. In this paper, we analyze the frequency and types of alterations in molecules of the RAS/RAF/MEK/ERK pathway in breast cancer, along with their prognostic and predictive impact in response to treatments such as chemotherapy, endocrine therapy, anti-HER2 therapy, and immunotherapy. Currently, with the aim of developing new drugs targeting this pathway, clear information is crucial for designing trials in breast cancer. This information is especially important to identify potential combinations of different agents to delay or overcome resistance in the different breast cancer subtypes. ABSTRACT: Although gene alterations of the RAS/RAF/MEK/ERK pathway are uncommon in breast cancer, this pathway is frequently activated in breast tumors, implying its role in tumor progression. We describe, after a revision of the literature, the frequency and types of gene alterations affecting this pathway in breast cancer by analyzing some public datasets from cBioPortal. Moreover, we consider their prognostic and predictive impact on treatment response, along with the role of transcriptomic predictors of RAS pathway activation. Our analysis shows that the driver alterations in RAS/RAF/MEK/ERK pathway-related genes are detected in 11% of primary breast cancers. The most frequently mutated genes are NF1 and KRAS, while copy number alterations mainly affect KRAS and BRAF, especially in basal-like tumors. The subgroup of patients carrying these alterations shows a worse prognosis; alterations in NF1 and RAF1 are associated with significantly reduced breast-cancer-specific survival in multivariate analysis. The literature review shows that the pathway is implicated, either by genetic or epigenetic alterations or by signaling network adaptations, in the mechanisms of sensitivity and resistance to a wide range of drugs used in the treatment of breast cancer. A thorough understanding of these alterations is critical for developing combination therapies that can delay or overcome drug resistance. |
format | Online Article Text |
id | pubmed-9653766 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-96537662022-11-15 The Predictive and Prognostic Role of RAS–RAF–MEK–ERK Pathway Alterations in Breast Cancer: Revision of the Literature and Comparison with the Analysis of Cancer Genomic Datasets Rocca, Andrea Braga, Luca Volpe, Maria Concetta Maiocchi, Serena Generali, Daniele Cancers (Basel) Review SIMPLE SUMMARY: The RAS/RAF/MEK/ERK pathway is implicated in fundamental processes frequently altered in tumors, such as cell proliferation and survival. In breast cancer, it is rarely affected by genomic alterations, but it is activated by membrane receptors or by epigenetic phenomena or readjustments in intracellular signaling networks. To date, drugs targeting molecules involved in this pathway have not been effective in the treatment of breast cancer: although successful in in vitro experiments, they fail in clinical trials. In this paper, we analyze the frequency and types of alterations in molecules of the RAS/RAF/MEK/ERK pathway in breast cancer, along with their prognostic and predictive impact in response to treatments such as chemotherapy, endocrine therapy, anti-HER2 therapy, and immunotherapy. Currently, with the aim of developing new drugs targeting this pathway, clear information is crucial for designing trials in breast cancer. This information is especially important to identify potential combinations of different agents to delay or overcome resistance in the different breast cancer subtypes. ABSTRACT: Although gene alterations of the RAS/RAF/MEK/ERK pathway are uncommon in breast cancer, this pathway is frequently activated in breast tumors, implying its role in tumor progression. We describe, after a revision of the literature, the frequency and types of gene alterations affecting this pathway in breast cancer by analyzing some public datasets from cBioPortal. Moreover, we consider their prognostic and predictive impact on treatment response, along with the role of transcriptomic predictors of RAS pathway activation. Our analysis shows that the driver alterations in RAS/RAF/MEK/ERK pathway-related genes are detected in 11% of primary breast cancers. The most frequently mutated genes are NF1 and KRAS, while copy number alterations mainly affect KRAS and BRAF, especially in basal-like tumors. The subgroup of patients carrying these alterations shows a worse prognosis; alterations in NF1 and RAF1 are associated with significantly reduced breast-cancer-specific survival in multivariate analysis. The literature review shows that the pathway is implicated, either by genetic or epigenetic alterations or by signaling network adaptations, in the mechanisms of sensitivity and resistance to a wide range of drugs used in the treatment of breast cancer. A thorough understanding of these alterations is critical for developing combination therapies that can delay or overcome drug resistance. MDPI 2022-10-28 /pmc/articles/PMC9653766/ /pubmed/36358725 http://dx.doi.org/10.3390/cancers14215306 Text en © 2022 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 | Review Rocca, Andrea Braga, Luca Volpe, Maria Concetta Maiocchi, Serena Generali, Daniele The Predictive and Prognostic Role of RAS–RAF–MEK–ERK Pathway Alterations in Breast Cancer: Revision of the Literature and Comparison with the Analysis of Cancer Genomic Datasets |
title | The Predictive and Prognostic Role of RAS–RAF–MEK–ERK Pathway Alterations in Breast Cancer: Revision of the Literature and Comparison with the Analysis of Cancer Genomic Datasets |
title_full | The Predictive and Prognostic Role of RAS–RAF–MEK–ERK Pathway Alterations in Breast Cancer: Revision of the Literature and Comparison with the Analysis of Cancer Genomic Datasets |
title_fullStr | The Predictive and Prognostic Role of RAS–RAF–MEK–ERK Pathway Alterations in Breast Cancer: Revision of the Literature and Comparison with the Analysis of Cancer Genomic Datasets |
title_full_unstemmed | The Predictive and Prognostic Role of RAS–RAF–MEK–ERK Pathway Alterations in Breast Cancer: Revision of the Literature and Comparison with the Analysis of Cancer Genomic Datasets |
title_short | The Predictive and Prognostic Role of RAS–RAF–MEK–ERK Pathway Alterations in Breast Cancer: Revision of the Literature and Comparison with the Analysis of Cancer Genomic Datasets |
title_sort | predictive and prognostic role of ras–raf–mek–erk pathway alterations in breast cancer: revision of the literature and comparison with the analysis of cancer genomic datasets |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9653766/ https://www.ncbi.nlm.nih.gov/pubmed/36358725 http://dx.doi.org/10.3390/cancers14215306 |
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