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Genome instability and pressure on non-homologous end joining drives chemotherapy resistance via a DNA repair crisis switch in triple negative breast cancer
Chemotherapy is used as a standard-of-care against cancers that display high levels of inherent genome instability. Chemotherapy induces DNA damage and intensifies pressure on the DNA repair pathways that can lead to deregulation. There is an urgent clinical need to be able to track the emergence of...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8210242/ https://www.ncbi.nlm.nih.gov/pubmed/34316709 http://dx.doi.org/10.1093/narcan/zcab022 |
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author | Wiegmans, Adrian P Ward, Ambber Ivanova, Ekaterina Duijf, Pascal H G Adams, Mark N Najib, Idris Mohd Van Oosterhout, Romy Sadowski, Martin C Kelly, Greg Morrical, Scott W O’Byrne, Ken Lee, Jason S Richard, Derek J |
author_facet | Wiegmans, Adrian P Ward, Ambber Ivanova, Ekaterina Duijf, Pascal H G Adams, Mark N Najib, Idris Mohd Van Oosterhout, Romy Sadowski, Martin C Kelly, Greg Morrical, Scott W O’Byrne, Ken Lee, Jason S Richard, Derek J |
author_sort | Wiegmans, Adrian P |
collection | PubMed |
description | Chemotherapy is used as a standard-of-care against cancers that display high levels of inherent genome instability. Chemotherapy induces DNA damage and intensifies pressure on the DNA repair pathways that can lead to deregulation. There is an urgent clinical need to be able to track the emergence of DNA repair driven chemotherapy resistance and tailor patient staging appropriately. There have been numerous studies into chemoresistance but to date no study has elucidated in detail the roles of the key DNA repair components in resistance associated with the frontline clinical combination of anthracyclines and taxanes together. In this study, we hypothesized that the emergence of chemotherapy resistance in triple negative breast cancer was driven by changes in functional signaling in the DNA repair pathways. We identified that consistent pressure on the non-homologous end joining pathway in the presence of genome instability causes failure of the key kinase DNA-PK, loss of p53 and compensation by p73. In-turn a switch to reliance on the homologous recombination pathway and RAD51 recombinase occurred to repair residual double strand DNA breaks. Further we demonstrate that RAD51 is an actionable target for resensitization to chemotherapy in resistant cells with a matched gene expression profile of resistance highlighted by homologous recombination in clinical samples. |
format | Online Article Text |
id | pubmed-8210242 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-82102422021-07-26 Genome instability and pressure on non-homologous end joining drives chemotherapy resistance via a DNA repair crisis switch in triple negative breast cancer Wiegmans, Adrian P Ward, Ambber Ivanova, Ekaterina Duijf, Pascal H G Adams, Mark N Najib, Idris Mohd Van Oosterhout, Romy Sadowski, Martin C Kelly, Greg Morrical, Scott W O’Byrne, Ken Lee, Jason S Richard, Derek J NAR Cancer DNA Damage Sensing and Repair Chemotherapy is used as a standard-of-care against cancers that display high levels of inherent genome instability. Chemotherapy induces DNA damage and intensifies pressure on the DNA repair pathways that can lead to deregulation. There is an urgent clinical need to be able to track the emergence of DNA repair driven chemotherapy resistance and tailor patient staging appropriately. There have been numerous studies into chemoresistance but to date no study has elucidated in detail the roles of the key DNA repair components in resistance associated with the frontline clinical combination of anthracyclines and taxanes together. In this study, we hypothesized that the emergence of chemotherapy resistance in triple negative breast cancer was driven by changes in functional signaling in the DNA repair pathways. We identified that consistent pressure on the non-homologous end joining pathway in the presence of genome instability causes failure of the key kinase DNA-PK, loss of p53 and compensation by p73. In-turn a switch to reliance on the homologous recombination pathway and RAD51 recombinase occurred to repair residual double strand DNA breaks. Further we demonstrate that RAD51 is an actionable target for resensitization to chemotherapy in resistant cells with a matched gene expression profile of resistance highlighted by homologous recombination in clinical samples. Oxford University Press 2021-06-15 /pmc/articles/PMC8210242/ /pubmed/34316709 http://dx.doi.org/10.1093/narcan/zcab022 Text en © The Author(s) 2021. Published by Oxford University Press on behalf of NAR Cancer. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | DNA Damage Sensing and Repair Wiegmans, Adrian P Ward, Ambber Ivanova, Ekaterina Duijf, Pascal H G Adams, Mark N Najib, Idris Mohd Van Oosterhout, Romy Sadowski, Martin C Kelly, Greg Morrical, Scott W O’Byrne, Ken Lee, Jason S Richard, Derek J Genome instability and pressure on non-homologous end joining drives chemotherapy resistance via a DNA repair crisis switch in triple negative breast cancer |
title | Genome instability and pressure on non-homologous end joining drives chemotherapy resistance via a DNA repair crisis switch in triple negative breast cancer |
title_full | Genome instability and pressure on non-homologous end joining drives chemotherapy resistance via a DNA repair crisis switch in triple negative breast cancer |
title_fullStr | Genome instability and pressure on non-homologous end joining drives chemotherapy resistance via a DNA repair crisis switch in triple negative breast cancer |
title_full_unstemmed | Genome instability and pressure on non-homologous end joining drives chemotherapy resistance via a DNA repair crisis switch in triple negative breast cancer |
title_short | Genome instability and pressure on non-homologous end joining drives chemotherapy resistance via a DNA repair crisis switch in triple negative breast cancer |
title_sort | genome instability and pressure on non-homologous end joining drives chemotherapy resistance via a dna repair crisis switch in triple negative breast cancer |
topic | DNA Damage Sensing and Repair |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8210242/ https://www.ncbi.nlm.nih.gov/pubmed/34316709 http://dx.doi.org/10.1093/narcan/zcab022 |
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