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PALB2 or BARD1 loss confers homologous recombination deficiency and PARP inhibitor sensitivity in prostate cancer

PARP inhibitors were recently approved for treatment of molecularly-defined subsets of metastatic castrate-resistant prostate cancer (mCRPC) patients. Although the PARP inhibitor olaparib was approved for use in patients with a mutation in one of fourteen genes, the mutation frequency of the genes v...

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Autores principales: Dillon, Kasia M., Bekele, Raie T., Sztupinszki, Zsofia, Hanlon, Timothy, Rafiei, Shahrzad, Szallasi, Zoltan, Choudhury, Atish D., Mouw, Kent W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9242979/
https://www.ncbi.nlm.nih.gov/pubmed/35768576
http://dx.doi.org/10.1038/s41698-022-00291-7
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author Dillon, Kasia M.
Bekele, Raie T.
Sztupinszki, Zsofia
Hanlon, Timothy
Rafiei, Shahrzad
Szallasi, Zoltan
Choudhury, Atish D.
Mouw, Kent W.
author_facet Dillon, Kasia M.
Bekele, Raie T.
Sztupinszki, Zsofia
Hanlon, Timothy
Rafiei, Shahrzad
Szallasi, Zoltan
Choudhury, Atish D.
Mouw, Kent W.
author_sort Dillon, Kasia M.
collection PubMed
description PARP inhibitors were recently approved for treatment of molecularly-defined subsets of metastatic castrate-resistant prostate cancer (mCRPC) patients. Although the PARP inhibitor olaparib was approved for use in patients with a mutation in one of fourteen genes, the mutation frequency of the genes varies widely in mCRPC and the impact of the less commonly altered genes on PARP inhibitor sensitivity is uncertain. We used functional approaches to directly test the impact of PALB2 and BARD1 loss on homologous recombination (HR) function and PARP inhibitor sensitivity in prostate cancer cell lines. PALB2 or BARD1 loss led to decreased HR function as measured by loss of radiation-induced Rad51 foci formation as well as decreased HR capacity in a cell-based reporter assay. PALB2 or BARD1 loss also significantly increased sensitivity to the PARP inhibitors olaparib and rucaparib across a panel of prostate cancer cell lines. These data support PALB2 and BARD1 loss as markers of clinically relevant PARP inhibitor sensitivity and highlight the potential to use functional approaches to complement and extend findings from clinical trials of targeted agents.
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spelling pubmed-92429792022-07-01 PALB2 or BARD1 loss confers homologous recombination deficiency and PARP inhibitor sensitivity in prostate cancer Dillon, Kasia M. Bekele, Raie T. Sztupinszki, Zsofia Hanlon, Timothy Rafiei, Shahrzad Szallasi, Zoltan Choudhury, Atish D. Mouw, Kent W. NPJ Precis Oncol Article PARP inhibitors were recently approved for treatment of molecularly-defined subsets of metastatic castrate-resistant prostate cancer (mCRPC) patients. Although the PARP inhibitor olaparib was approved for use in patients with a mutation in one of fourteen genes, the mutation frequency of the genes varies widely in mCRPC and the impact of the less commonly altered genes on PARP inhibitor sensitivity is uncertain. We used functional approaches to directly test the impact of PALB2 and BARD1 loss on homologous recombination (HR) function and PARP inhibitor sensitivity in prostate cancer cell lines. PALB2 or BARD1 loss led to decreased HR function as measured by loss of radiation-induced Rad51 foci formation as well as decreased HR capacity in a cell-based reporter assay. PALB2 or BARD1 loss also significantly increased sensitivity to the PARP inhibitors olaparib and rucaparib across a panel of prostate cancer cell lines. These data support PALB2 and BARD1 loss as markers of clinically relevant PARP inhibitor sensitivity and highlight the potential to use functional approaches to complement and extend findings from clinical trials of targeted agents. Nature Publishing Group UK 2022-06-29 /pmc/articles/PMC9242979/ /pubmed/35768576 http://dx.doi.org/10.1038/s41698-022-00291-7 Text en © The Author(s) 2022 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
Dillon, Kasia M.
Bekele, Raie T.
Sztupinszki, Zsofia
Hanlon, Timothy
Rafiei, Shahrzad
Szallasi, Zoltan
Choudhury, Atish D.
Mouw, Kent W.
PALB2 or BARD1 loss confers homologous recombination deficiency and PARP inhibitor sensitivity in prostate cancer
title PALB2 or BARD1 loss confers homologous recombination deficiency and PARP inhibitor sensitivity in prostate cancer
title_full PALB2 or BARD1 loss confers homologous recombination deficiency and PARP inhibitor sensitivity in prostate cancer
title_fullStr PALB2 or BARD1 loss confers homologous recombination deficiency and PARP inhibitor sensitivity in prostate cancer
title_full_unstemmed PALB2 or BARD1 loss confers homologous recombination deficiency and PARP inhibitor sensitivity in prostate cancer
title_short PALB2 or BARD1 loss confers homologous recombination deficiency and PARP inhibitor sensitivity in prostate cancer
title_sort palb2 or bard1 loss confers homologous recombination deficiency and parp inhibitor sensitivity in prostate cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9242979/
https://www.ncbi.nlm.nih.gov/pubmed/35768576
http://dx.doi.org/10.1038/s41698-022-00291-7
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