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

Abstract 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 gatekee...

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Autores principales:	Craig Davison, Roisin Morelli, Catherine Knowlson, Melanie McKechnie, Robbie Carson, Xanthi Stachtea, Kylie A. McLaughlin, Vivien E. Prise, Kienan Savage, Richard H. Wilson, Karl A. Mulligan, Peter M. Wilson, Robert D. Ladner, Melissa J. LaBonte
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/d3cd97feebf847539e7f6183d26a60c8
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spelling	oai:doaj.org-article:d3cd97feebf847539e7f6183d26a60c82021-12-02T14:22:42ZTargeting nucleotide metabolism enhances the efficacy of anthracyclines and anti-metabolites in triple-negative breast cancer10.1038/s41523-021-00245-52374-4677https://doaj.org/article/d3cd97feebf847539e7f6183d26a60c82021-04-01T00:00:00Zhttps://doi.org/10.1038/s41523-021-00245-5https://doaj.org/toc/2374-4677Abstract 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.Craig DavisonRoisin MorelliCatherine KnowlsonMelanie McKechnieRobbie CarsonXanthi StachteaKylie A. McLaughlinVivien E. PriseKienan SavageRichard H. WilsonKarl A. MulliganPeter M. WilsonRobert D. LadnerMelissa J. LaBonteNature PortfolioarticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENnpj Breast Cancer, Vol 7, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Craig Davison Roisin Morelli Catherine Knowlson Melanie McKechnie Robbie Carson Xanthi Stachtea Kylie A. McLaughlin Vivien E. Prise Kienan Savage Richard H. Wilson Karl A. Mulligan Peter M. Wilson Robert D. Ladner Melissa J. LaBonte Targeting nucleotide metabolism enhances the efficacy of anthracyclines and anti-metabolites in triple-negative breast cancer
description	Abstract 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.
format	article
author	Craig Davison Roisin Morelli Catherine Knowlson Melanie McKechnie Robbie Carson Xanthi Stachtea Kylie A. McLaughlin Vivien E. Prise Kienan Savage Richard H. Wilson Karl A. Mulligan Peter M. Wilson Robert D. Ladner Melissa J. LaBonte
author_facet	Craig Davison Roisin Morelli Catherine Knowlson Melanie McKechnie Robbie Carson Xanthi Stachtea Kylie A. McLaughlin Vivien E. Prise Kienan Savage Richard H. Wilson Karl A. Mulligan Peter M. Wilson Robert D. Ladner Melissa J. LaBonte
author_sort	Craig Davison
title	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_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_sort	targeting nucleotide metabolism enhances the efficacy of anthracyclines and anti-metabolites in triple-negative breast cancer
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/d3cd97feebf847539e7f6183d26a60c8
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Targeting nucleotide metabolism enhances the efficacy of anthracyclines and anti-metabolites in triple-negative breast cancer

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