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Exploiting DNA repair defects in colorectal cancer
Colorectal cancer (CRC) is the third leading cause of cancer‐related deaths worldwide. Therapies that take advantage of defects in DNA repair pathways have been explored in the context of breast, ovarian, and other tumor types, but not yet systematically in CRC. At present, only immune checkpoint bl...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441925/ https://www.ncbi.nlm.nih.gov/pubmed/30714316 http://dx.doi.org/10.1002/1878-0261.12467 |
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author | Reilly, Nicole M. Novara, Luca Di Nicolantonio, Federica Bardelli, Alberto |
author_facet | Reilly, Nicole M. Novara, Luca Di Nicolantonio, Federica Bardelli, Alberto |
author_sort | Reilly, Nicole M. |
collection | PubMed |
description | Colorectal cancer (CRC) is the third leading cause of cancer‐related deaths worldwide. Therapies that take advantage of defects in DNA repair pathways have been explored in the context of breast, ovarian, and other tumor types, but not yet systematically in CRC. At present, only immune checkpoint blockade therapies have been FDA approved for use in mismatch repair‐deficient colorectal tumors. Here, we discuss how systematic identification of alterations in DNA repair genes could provide new therapeutic opportunities for CRCs. Analysis of The Cancer Genome Atlas Colon Adenocarcinoma (TCGA‐COAD) and Rectal Adenocarcinoma (TCGA‐READ) PanCancer Atlas datasets identified 141 (out of 528) cases with putative driver mutations in 29 genes associated with DNA damage response and repair, including the mismatch repair and homologous recombination pathways. Genetic defects in these pathways might confer repair‐deficient characteristics, such as genomic instability in the absence of homologous recombination, which can be exploited. For example, inhibitors of poly(ADP)‐ribose polymerase are effectively used to treat cancers that carry mutations in BRCA1 and/or BRCA2 and have shown promising results in CRC preclinical studies. HR deficiency can also occur in cells with no detectable BRCA1/BRCA2 mutations but exhibiting BRCA‐like phenotypes. DNA repair‐targeting therapies, such as ATR and CHK1 inhibitors (which are most effective against cancers carrying ATM mutations), can be used in combination with current genotoxic chemotherapies in CRCs to further improve therapy response. Finally, therapies that target alternative DNA repair mechanisms, such as thiopurines, also have the potential to confer increased sensitivity to current chemotherapy regimens, thus expanding the spectrum of therapy options and potentially improving clinical outcomes for CRC patients. |
format | Online Article Text |
id | pubmed-6441925 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-64419252019-04-11 Exploiting DNA repair defects in colorectal cancer Reilly, Nicole M. Novara, Luca Di Nicolantonio, Federica Bardelli, Alberto Mol Oncol Review Articles Colorectal cancer (CRC) is the third leading cause of cancer‐related deaths worldwide. Therapies that take advantage of defects in DNA repair pathways have been explored in the context of breast, ovarian, and other tumor types, but not yet systematically in CRC. At present, only immune checkpoint blockade therapies have been FDA approved for use in mismatch repair‐deficient colorectal tumors. Here, we discuss how systematic identification of alterations in DNA repair genes could provide new therapeutic opportunities for CRCs. Analysis of The Cancer Genome Atlas Colon Adenocarcinoma (TCGA‐COAD) and Rectal Adenocarcinoma (TCGA‐READ) PanCancer Atlas datasets identified 141 (out of 528) cases with putative driver mutations in 29 genes associated with DNA damage response and repair, including the mismatch repair and homologous recombination pathways. Genetic defects in these pathways might confer repair‐deficient characteristics, such as genomic instability in the absence of homologous recombination, which can be exploited. For example, inhibitors of poly(ADP)‐ribose polymerase are effectively used to treat cancers that carry mutations in BRCA1 and/or BRCA2 and have shown promising results in CRC preclinical studies. HR deficiency can also occur in cells with no detectable BRCA1/BRCA2 mutations but exhibiting BRCA‐like phenotypes. DNA repair‐targeting therapies, such as ATR and CHK1 inhibitors (which are most effective against cancers carrying ATM mutations), can be used in combination with current genotoxic chemotherapies in CRCs to further improve therapy response. Finally, therapies that target alternative DNA repair mechanisms, such as thiopurines, also have the potential to confer increased sensitivity to current chemotherapy regimens, thus expanding the spectrum of therapy options and potentially improving clinical outcomes for CRC patients. John Wiley and Sons Inc. 2019-03-02 2019-04 /pmc/articles/PMC6441925/ /pubmed/30714316 http://dx.doi.org/10.1002/1878-0261.12467 Text en © 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Review Articles Reilly, Nicole M. Novara, Luca Di Nicolantonio, Federica Bardelli, Alberto Exploiting DNA repair defects in colorectal cancer |
title | Exploiting DNA repair defects in colorectal cancer |
title_full | Exploiting DNA repair defects in colorectal cancer |
title_fullStr | Exploiting DNA repair defects in colorectal cancer |
title_full_unstemmed | Exploiting DNA repair defects in colorectal cancer |
title_short | Exploiting DNA repair defects in colorectal cancer |
title_sort | exploiting dna repair defects in colorectal cancer |
topic | Review Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441925/ https://www.ncbi.nlm.nih.gov/pubmed/30714316 http://dx.doi.org/10.1002/1878-0261.12467 |
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