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Targeting nucleotide metabolism enhances the efficacy of anthracyclines and anti-metabolites in triple-negative breast cancer

Triple-negative breast cancer (TNBC) remains the most lethal breast cancer subtype with poor response rates to the current chemotherapies and a lack of additional effective treatment options. We have identified deoxyuridine 5′-triphosphate nucleotidohydrolase (dUTPase) as a critical gatekeeper that...

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Autores principales: Davison, Craig, Morelli, Roisin, Knowlson, Catherine, McKechnie, Melanie, Carson, Robbie, Stachtea, Xanthi, McLaughlin, Kylie A., Prise, Vivien E., Savage, Kienan, Wilson, Richard H., Mulligan, Karl A., Wilson, Peter M., Ladner, Robert D., LaBonte, Melissa J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024381/
https://www.ncbi.nlm.nih.gov/pubmed/33824328
http://dx.doi.org/10.1038/s41523-021-00245-5
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author Davison, Craig
Morelli, Roisin
Knowlson, Catherine
McKechnie, Melanie
Carson, Robbie
Stachtea, Xanthi
McLaughlin, Kylie A.
Prise, Vivien E.
Savage, Kienan
Wilson, Richard H.
Mulligan, Karl A.
Wilson, Peter M.
Ladner, Robert D.
LaBonte, Melissa J.
author_facet Davison, Craig
Morelli, Roisin
Knowlson, Catherine
McKechnie, Melanie
Carson, Robbie
Stachtea, Xanthi
McLaughlin, Kylie A.
Prise, Vivien E.
Savage, Kienan
Wilson, Richard H.
Mulligan, Karl A.
Wilson, Peter M.
Ladner, Robert D.
LaBonte, Melissa J.
author_sort Davison, Craig
collection PubMed
description Triple-negative breast cancer (TNBC) remains the most lethal breast cancer subtype with poor response rates to the current chemotherapies and a lack of additional effective treatment options. We have identified deoxyuridine 5′-triphosphate nucleotidohydrolase (dUTPase) as a critical gatekeeper that protects tumour DNA from the genotoxic misincorporation of uracil during treatment with standard chemotherapeutic agents commonly used in the FEC regimen. dUTPase catalyses the hydrolytic dephosphorylation of deoxyuridine triphosphate (dUTP) to deoxyuridine monophosphate (dUMP), providing dUMP for thymidylate synthase as part of the thymidylate biosynthesis pathway and maintaining low intracellular dUTP concentrations. This is crucial as DNA polymerase cannot distinguish between dUTP and deoxythymidylate triphosphate (dTTP), leading to dUTP misincorporation into DNA. Targeting dUTPase and inducing uracil misincorporation during the repair of DNA damage induced by fluoropyrimidines or anthracyclines represents an effective strategy to induce cell lethality. dUTPase inhibition significantly sensitised TNBC cell lines to fluoropyrimidines and anthracyclines through imbalanced nucleotide pools and increased DNA damage leading to decreased proliferation and increased cell death. These results suggest that repair of treatment-mediated DNA damage requires dUTPase to prevent uracil misincorporation and that inhibition of dUTPase is a promising strategy to enhance the efficacy of TNBC chemotherapy.
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spelling pubmed-80243812021-04-21 Targeting nucleotide metabolism enhances the efficacy of anthracyclines and anti-metabolites in triple-negative breast cancer Davison, Craig Morelli, Roisin Knowlson, Catherine McKechnie, Melanie Carson, Robbie Stachtea, Xanthi McLaughlin, Kylie A. Prise, Vivien E. Savage, Kienan Wilson, Richard H. Mulligan, Karl A. Wilson, Peter M. Ladner, Robert D. LaBonte, Melissa J. NPJ Breast Cancer Article Triple-negative breast cancer (TNBC) remains the most lethal breast cancer subtype with poor response rates to the current chemotherapies and a lack of additional effective treatment options. We have identified deoxyuridine 5′-triphosphate nucleotidohydrolase (dUTPase) as a critical gatekeeper that protects tumour DNA from the genotoxic misincorporation of uracil during treatment with standard chemotherapeutic agents commonly used in the FEC regimen. dUTPase catalyses the hydrolytic dephosphorylation of deoxyuridine triphosphate (dUTP) to deoxyuridine monophosphate (dUMP), providing dUMP for thymidylate synthase as part of the thymidylate biosynthesis pathway and maintaining low intracellular dUTP concentrations. This is crucial as DNA polymerase cannot distinguish between dUTP and deoxythymidylate triphosphate (dTTP), leading to dUTP misincorporation into DNA. Targeting dUTPase and inducing uracil misincorporation during the repair of DNA damage induced by fluoropyrimidines or anthracyclines represents an effective strategy to induce cell lethality. dUTPase inhibition significantly sensitised TNBC cell lines to fluoropyrimidines and anthracyclines through imbalanced nucleotide pools and increased DNA damage leading to decreased proliferation and increased cell death. These results suggest that repair of treatment-mediated DNA damage requires dUTPase to prevent uracil misincorporation and that inhibition of dUTPase is a promising strategy to enhance the efficacy of TNBC chemotherapy. Nature Publishing Group UK 2021-04-06 /pmc/articles/PMC8024381/ /pubmed/33824328 http://dx.doi.org/10.1038/s41523-021-00245-5 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
Davison, Craig
Morelli, Roisin
Knowlson, Catherine
McKechnie, Melanie
Carson, Robbie
Stachtea, Xanthi
McLaughlin, Kylie A.
Prise, Vivien E.
Savage, Kienan
Wilson, Richard H.
Mulligan, Karl A.
Wilson, Peter M.
Ladner, Robert D.
LaBonte, Melissa J.
Targeting nucleotide metabolism enhances the efficacy of anthracyclines and anti-metabolites in triple-negative breast cancer
title Targeting nucleotide metabolism enhances the efficacy of anthracyclines and anti-metabolites in triple-negative breast cancer
title_full Targeting nucleotide metabolism enhances the efficacy of anthracyclines and anti-metabolites in triple-negative breast cancer
title_fullStr Targeting nucleotide metabolism enhances the efficacy of anthracyclines and anti-metabolites in triple-negative breast cancer
title_full_unstemmed Targeting nucleotide metabolism enhances the efficacy of anthracyclines and anti-metabolites in triple-negative breast cancer
title_short Targeting nucleotide metabolism enhances the efficacy of anthracyclines and anti-metabolites in triple-negative breast cancer
title_sort targeting nucleotide metabolism enhances the efficacy of anthracyclines and anti-metabolites in triple-negative breast cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024381/
https://www.ncbi.nlm.nih.gov/pubmed/33824328
http://dx.doi.org/10.1038/s41523-021-00245-5
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