The Role of ATR Inhibitors in Ovarian Cancer: Investigating Predictive Biomarkers of Response

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Ataxia telangiectasia and Rad-3 related kinase (ATR) is crucial for DNA damage response and a target for cancer therapy.
• ATR inhibitors (ATRi) are being investigated for cancer treatment, particularly in ovarian cancer where sensitivity determinants are common.

Purpose of the Study:

• To investigate the cytotoxicity of the ATR inhibitor VE-821 in human ovarian cancer cell lines.
• To identify molecular determinants of sensitivity to VE-821, focusing on gene mutations and protein expression.
• To assess the role of replication stress (RS) as a predictive biomarker for ATRi response.

Main Methods:

• Cytotoxicity assays using VE-821 on a panel of ovarian cancer cell lines (high-grade serous vs. non-HGS).
• Analysis of previously identified sensitivity determinants (TP53, ATM, BRCA1) and protein expression levels (RAD51, TopBP1, APOBEC3B).
• Measurement of replication stress markers (pRPA Ser4/8, γH2AX) via immunofluorescence.

Main Results:

• High-grade serous (HGS) ovarian cancer cell lines were significantly more sensitive to VE-821 than non-HGS lines.
• TP53, ATM, and BRCA1 mutations were not predictive of sensitivity.
• Low RAD51, TopBP1, and APOBEC3B protein expression correlated with increased VE-821 sensitivity.
• HGS cells exhibited higher levels of replication stress, which independently predicted sensitivity to VE-821.

Conclusions:

• Replication stress biomarkers, rather than specific gene mutations, may be superior predictors of ATR inhibitor response in ovarian cancer.
• Functional assessment of replication stress could guide ATRi therapy selection in ovarian and potentially other cancers.