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Pin1 inhibition improves the efficacy of ralaniten compounds that bind to the N-terminal domain of androgen receptor

Therapies for lethal castration-resistant prostate cancer (CRPC) are an unmet medical need. One mechanism underlying CRPC and resistance to hormonal therapies is the expression of constitutively active splice variant(s) of androgen receptor (AR-Vs) that lack its C-terminus ligand-binding domain. Tra...

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Autores principales: Leung, Jacky K., Imamura, Yusuke, Kato, Minoru, Wang, Jun, Mawji, Nasrin R., Sadar, Marianne D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985297/
https://www.ncbi.nlm.nih.gov/pubmed/33753863
http://dx.doi.org/10.1038/s42003-021-01927-3
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author Leung, Jacky K.
Imamura, Yusuke
Kato, Minoru
Wang, Jun
Mawji, Nasrin R.
Sadar, Marianne D.
author_facet Leung, Jacky K.
Imamura, Yusuke
Kato, Minoru
Wang, Jun
Mawji, Nasrin R.
Sadar, Marianne D.
author_sort Leung, Jacky K.
collection PubMed
description Therapies for lethal castration-resistant prostate cancer (CRPC) are an unmet medical need. One mechanism underlying CRPC and resistance to hormonal therapies is the expression of constitutively active splice variant(s) of androgen receptor (AR-Vs) that lack its C-terminus ligand-binding domain. Transcriptional activities of AR-Vs and full-length AR reside in its N-terminal domain (NTD). Ralaniten is the only drug proven to bind AR NTD, and it showed promise of efficacy in Phase 1 trials. The peptidyl-prolyl isomerase Pin1 is frequently overexpressed in prostate cancer. Here we show that Pin1 interacted with AR NTD. The inhibition of Pin1 expression or its activity selectively reduced the transcriptional activities of full-length AR and AR-V7. Combination of Pin1 inhibitor with ralaniten promoted cell cycle arrest and had improved antitumor activity against CRPC xenografts in vivo compared to individual monotherapies. These findings support the rationale for therapy that combines a Pin1 inhibitor with ralaniten for treating CRPC.
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spelling pubmed-79852972021-04-16 Pin1 inhibition improves the efficacy of ralaniten compounds that bind to the N-terminal domain of androgen receptor Leung, Jacky K. Imamura, Yusuke Kato, Minoru Wang, Jun Mawji, Nasrin R. Sadar, Marianne D. Commun Biol Article Therapies for lethal castration-resistant prostate cancer (CRPC) are an unmet medical need. One mechanism underlying CRPC and resistance to hormonal therapies is the expression of constitutively active splice variant(s) of androgen receptor (AR-Vs) that lack its C-terminus ligand-binding domain. Transcriptional activities of AR-Vs and full-length AR reside in its N-terminal domain (NTD). Ralaniten is the only drug proven to bind AR NTD, and it showed promise of efficacy in Phase 1 trials. The peptidyl-prolyl isomerase Pin1 is frequently overexpressed in prostate cancer. Here we show that Pin1 interacted with AR NTD. The inhibition of Pin1 expression or its activity selectively reduced the transcriptional activities of full-length AR and AR-V7. Combination of Pin1 inhibitor with ralaniten promoted cell cycle arrest and had improved antitumor activity against CRPC xenografts in vivo compared to individual monotherapies. These findings support the rationale for therapy that combines a Pin1 inhibitor with ralaniten for treating CRPC. Nature Publishing Group UK 2021-03-22 /pmc/articles/PMC7985297/ /pubmed/33753863 http://dx.doi.org/10.1038/s42003-021-01927-3 Text en © The Author(s) 2021 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/.
spellingShingle Article
Leung, Jacky K.
Imamura, Yusuke
Kato, Minoru
Wang, Jun
Mawji, Nasrin R.
Sadar, Marianne D.
Pin1 inhibition improves the efficacy of ralaniten compounds that bind to the N-terminal domain of androgen receptor
title Pin1 inhibition improves the efficacy of ralaniten compounds that bind to the N-terminal domain of androgen receptor
title_full Pin1 inhibition improves the efficacy of ralaniten compounds that bind to the N-terminal domain of androgen receptor
title_fullStr Pin1 inhibition improves the efficacy of ralaniten compounds that bind to the N-terminal domain of androgen receptor
title_full_unstemmed Pin1 inhibition improves the efficacy of ralaniten compounds that bind to the N-terminal domain of androgen receptor
title_short Pin1 inhibition improves the efficacy of ralaniten compounds that bind to the N-terminal domain of androgen receptor
title_sort pin1 inhibition improves the efficacy of ralaniten compounds that bind to the n-terminal domain of androgen receptor
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985297/
https://www.ncbi.nlm.nih.gov/pubmed/33753863
http://dx.doi.org/10.1038/s42003-021-01927-3
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