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
Medicine, Dentistry and Biomedical Sciences: Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK.
CV6 Therapeutics (NI) Ltd, Belfast, UK.
NPJ Breast Cancer. 2021 Apr 6;7(1):38. doi: 10.1038/s41523-021-00245-5.
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.
三阴性乳腺癌（TNBC）仍然是最致命的乳腺癌亚型，对当前化疗的反应率较低，且缺乏其他有效的治疗选择。我们已确定脱氧尿苷5'-三磷酸核苷酸水解酶（dUTPase）是一种关键的把关蛋白，在使用FEC方案中常用的标准化疗药物治疗期间，它可保护肿瘤DNA免受尿嘧啶的基因毒性错误掺入。dUTPase催化脱氧尿苷三磷酸（dUTP）水解去磷酸化为脱氧尿苷单磷酸（dUMP），作为胸苷酸生物合成途径的一部分为胸苷酸合成酶提供dUMP，并维持细胞内低浓度的dUTP。这一点至关重要，因为DNA聚合酶无法区分dUTP和脱氧胸苷三磷酸（dTTP），会导致dUTP错误掺入DNA。在氟嘧啶或蒽环类药物诱导的DNA损伤修复过程中靶向dUTPase并诱导尿嘧啶错误掺入是诱导细胞死亡的有效策略。dUTPase抑制通过核苷酸池失衡和增加DNA损伤，显著使TNBC细胞系对氟嘧啶和蒽环类药物敏感，导致细胞增殖减少和细胞死亡增加。这些结果表明，治疗介导的DNA损伤修复需要dUTPase来防止尿嘧啶错误掺入，并且抑制dUTPase是提高TNBC化疗疗效的一种有前景的策略。
