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Lookup NU author(s): Alice Bradbury, Professor Nicola CurtinORCiD, Dr Yvette Drew
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Ataxia telangiectasia and Rad-3 related kinase (ATR) signals DNA lesions and replication stress (RS) to the S and G2/M checkpoints and DNA repair pathways making it a promising target to exploit the dysregulated DNA damage response in cancer. ATR inhibitors (ATRi) are under clinical investigation as monotherapy and in combination with other anticancer agents. Molecular determinants of sensitivity to ATRi are common in ovarian cancer, suggesting the therapeutic potential of ATRi. We investigated the cytotoxicity of the ATRi, VE-821, in a panel of human ovarian cancer cell lines. High grade serous (HGS) cell lines were significantly more sensitive to VE-821 than non-HGS (p ≤ 0.0001) but previously identified determinants of sensitivity (TP53, ATM and BRCA1) were not predictive. Only low RAD51 (p = 0.041), TopBP1 (p = 0.026) and APOBEC3B (p = 0.015) protein expression were associated with increased VE-821 sensitivity. HGS cells had increased levels of RS (pRPASer4/8 and γH2AX nuclear immunofluorescence), and elevated RS predicted sensitivity to VE-821 independently of the cell line subtype. These data suggest that functional assessment of RS biomarkers may be a better predictive biomarker of ATRi response than any single aberrant gene in ovarian cancer and potentially other cancers.
Author(s): Bradbury A, Zenke FT, Curtin NJ, Drew Y
Publication type: Article
Publication status: Published
Journal: Cells
Year: 2022
Volume: 11
Issue: 15
Online publication date: 01/08/2022
Acceptance date: 26/07/2022
Date deposited: 05/09/2022
ISSN (electronic): 2073-4409
Publisher: MDPI
URL: https://doi.org/10.3390/cells11152361
DOI: 10.3390/cells11152361
PubMed id: 35954206
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