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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2021-04-01
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doaj-d3cd97feebf847539e7f6183d26a60c82021-04-11T11:03:47ZengNature Publishing Groupnpj Breast Cancer2374-46772021-04-017111310.1038/s41523-021-00245-5Targeting nucleotide metabolism enhances the efficacy of anthracyclines and anti-metabolites in triple-negative breast cancerCraig Davison0Roisin Morelli1Catherine Knowlson2Melanie McKechnie3Robbie Carson4Xanthi Stachtea5Kylie A. McLaughlin6Vivien E. Prise7Kienan Savage8Richard H. Wilson9Karl A. Mulligan10Peter M. Wilson11Robert D. Ladner12Melissa J. LaBonte13Medicine, Dentistry and Biomedical Sciences: Patrick G Johnston Centre for Cancer Research, Queen’s University BelfastMedicine, Dentistry and Biomedical Sciences: Patrick G Johnston Centre for Cancer Research, Queen’s University BelfastMedicine, Dentistry and Biomedical Sciences: Patrick G Johnston Centre for Cancer Research, Queen’s University BelfastMedicine, Dentistry and Biomedical Sciences: Patrick G Johnston Centre for Cancer Research, Queen’s University BelfastMedicine, Dentistry and Biomedical Sciences: Patrick G Johnston Centre for Cancer Research, Queen’s University BelfastMedicine, Dentistry and Biomedical Sciences: Patrick G Johnston Centre for Cancer Research, Queen’s University BelfastCV6 Therapeutics (NI) LtdCV6 Therapeutics (NI) LtdMedicine, Dentistry and Biomedical Sciences: Patrick G Johnston Centre for Cancer Research, Queen’s University BelfastTranslational Research Centre, University of GlasgowCV6 Therapeutics (NI) LtdCV6 Therapeutics (NI) LtdMedicine, Dentistry and Biomedical Sciences: Patrick G Johnston Centre for Cancer Research, Queen’s University BelfastMedicine, Dentistry and Biomedical Sciences: Patrick G Johnston Centre for Cancer Research, Queen’s University BelfastAbstract 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.https://doi.org/10.1038/s41523-021-00245-5 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
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 |
spellingShingle |
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 npj Breast Cancer |
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 Publishing Group |
series |
npj Breast Cancer |
issn |
2374-4677 |
publishDate |
2021-04-01 |
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. |
url |
https://doi.org/10.1038/s41523-021-00245-5 |
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