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A Review of the Pathophysiological Mechanisms Underlying Castration-resistant Prostate Cancer
Androgen deprivation therapy or ADT is one of the cornerstones of management of locally advanced or metastatic prostate cancer, alongside radiation therapy. However, despite early response, most advanced prostate cancers progress into an androgen unresponsive or castrate resistant state, which hithe...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Dove
2021
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256377/ https://www.ncbi.nlm.nih.gov/pubmed/34235102 http://dx.doi.org/10.2147/RRU.S264722 |
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author | Crowley, Fionnuala Sterpi, Michelle Buckley, Conor Margetich, Lauren Handa, Shivani Dovey, Zach |
author_facet | Crowley, Fionnuala Sterpi, Michelle Buckley, Conor Margetich, Lauren Handa, Shivani Dovey, Zach |
author_sort | Crowley, Fionnuala |
collection | PubMed |
description | Androgen deprivation therapy or ADT is one of the cornerstones of management of locally advanced or metastatic prostate cancer, alongside radiation therapy. However, despite early response, most advanced prostate cancers progress into an androgen unresponsive or castrate resistant state, which hitherto remains an incurable entity and the second leading cause of cancer-related mortality in men in the US. Recent advances have uncovered multiple complex and intermingled mechanisms underlying this transformation. While most of these mechanisms revolve around androgen receptor (AR) signaling, novel pathways which act independently of the androgen axis are also being discovered. The aim of this article is to review the pathophysiological mechanisms that help bypass the apoptotic effects of ADT to create castrate resistance. The article discusses castrate resistance mechanisms under two categories: 1. Direct AR dependent pathways such as amplification or gain of function mutations in AR, development of functional splice variants, posttranslational regulation, and pro-oncogenic modulation in the expression of coactivators vs corepressors of AR. 2. Ancillary pathways involving RAS/MAP kinase, TGF-beta/SMAD pathway, FGF signaling, JAK/STAT pathway, Wnt-Beta catenin and hedgehog signaling as well as the role of cell adhesion molecules and G-protein coupled receptors. miRNAs are also briefly discussed. Understanding the mechanisms involved in the development and progression of castration-resistant prostate cancer is paramount to the development of targeted agents to overcome these mechanisms. A number of targeted agents are currently in development. As we strive for more personalized treatment across oncology care, treatment regimens will need to be tailored based on the type of CRPC and the underlying mechanism of castration resistance. |
format | Online Article Text |
id | pubmed-8256377 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Dove |
record_format | MEDLINE/PubMed |
spelling | pubmed-82563772021-07-06 A Review of the Pathophysiological Mechanisms Underlying Castration-resistant Prostate Cancer Crowley, Fionnuala Sterpi, Michelle Buckley, Conor Margetich, Lauren Handa, Shivani Dovey, Zach Res Rep Urol Review Androgen deprivation therapy or ADT is one of the cornerstones of management of locally advanced or metastatic prostate cancer, alongside radiation therapy. However, despite early response, most advanced prostate cancers progress into an androgen unresponsive or castrate resistant state, which hitherto remains an incurable entity and the second leading cause of cancer-related mortality in men in the US. Recent advances have uncovered multiple complex and intermingled mechanisms underlying this transformation. While most of these mechanisms revolve around androgen receptor (AR) signaling, novel pathways which act independently of the androgen axis are also being discovered. The aim of this article is to review the pathophysiological mechanisms that help bypass the apoptotic effects of ADT to create castrate resistance. The article discusses castrate resistance mechanisms under two categories: 1. Direct AR dependent pathways such as amplification or gain of function mutations in AR, development of functional splice variants, posttranslational regulation, and pro-oncogenic modulation in the expression of coactivators vs corepressors of AR. 2. Ancillary pathways involving RAS/MAP kinase, TGF-beta/SMAD pathway, FGF signaling, JAK/STAT pathway, Wnt-Beta catenin and hedgehog signaling as well as the role of cell adhesion molecules and G-protein coupled receptors. miRNAs are also briefly discussed. Understanding the mechanisms involved in the development and progression of castration-resistant prostate cancer is paramount to the development of targeted agents to overcome these mechanisms. A number of targeted agents are currently in development. As we strive for more personalized treatment across oncology care, treatment regimens will need to be tailored based on the type of CRPC and the underlying mechanism of castration resistance. Dove 2021-06-30 /pmc/articles/PMC8256377/ /pubmed/34235102 http://dx.doi.org/10.2147/RRU.S264722 Text en © 2021 Crowley et al. https://creativecommons.org/licenses/by-nc/3.0/This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/ (https://creativecommons.org/licenses/by-nc/3.0/) ). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). |
spellingShingle | Review Crowley, Fionnuala Sterpi, Michelle Buckley, Conor Margetich, Lauren Handa, Shivani Dovey, Zach A Review of the Pathophysiological Mechanisms Underlying Castration-resistant Prostate Cancer |
title | A Review of the Pathophysiological Mechanisms Underlying Castration-resistant Prostate Cancer |
title_full | A Review of the Pathophysiological Mechanisms Underlying Castration-resistant Prostate Cancer |
title_fullStr | A Review of the Pathophysiological Mechanisms Underlying Castration-resistant Prostate Cancer |
title_full_unstemmed | A Review of the Pathophysiological Mechanisms Underlying Castration-resistant Prostate Cancer |
title_short | A Review of the Pathophysiological Mechanisms Underlying Castration-resistant Prostate Cancer |
title_sort | review of the pathophysiological mechanisms underlying castration-resistant prostate cancer |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256377/ https://www.ncbi.nlm.nih.gov/pubmed/34235102 http://dx.doi.org/10.2147/RRU.S264722 |
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