Common cancer-associated imbalances in the DNA damage response confer sensitivity to single agent ATR inhibition

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• ATR kinase is crucial for signaling DNA damage and replication stress to cell cycle checkpoints.
• Cancer cells with DNA damage response (DDR) defects may be vulnerable to ATR inhibitors.
• ATR inhibitors are being investigated as a targeted cancer therapy approach.

Purpose of the Study:

• To determine the cytotoxicity of the ATR inhibitor VE-821 in cells with DDR imbalances.
• To investigate how defects in homologous recombination repair (HRR) and base excision repair (BER) affect sensitivity to VE-821.
• To explore the role of DNA-PKcs expression in cellular response to ATR inhibition.

Main Methods:

• Cytotoxicity assays using isogenically matched cells with varying DDR defects.
• Cell cycle arrest, DNA damage accumulation, and DNA repair assays following VE-821 treatment.
• RAD51 focus formation assay to assess HRR suppression.

Main Results:

• Defects in HRR (ATM, BRCA2, XRCC3) and BER (XRCC1) conferred sensitivity to VE-821.
• Loss of Ku80 led to hypersensitivity to VE-821, while loss of DNA-PKcs did not.
• High DNA-PKcs expression correlated with increased VE-821 cytotoxicity, replicative stress, and suppressed HRR.

Conclusions:

• Defects in HRR and BER, and high DNA-PKcs expression are common in cancer and predict sensitivity to ATR inhibitor monotherapy.
• These factors may serve as predictive biomarkers for personalized medicine strategies targeting ATR.
• ATR inhibition demonstrates potential as a monotherapy for specific cancer subtypes with DDR alterations.