A consensus set of genetic vulnerabilities to ATR inhibition

Area of Science:

• Genetics
• Molecular Biology
• Cancer Biology

Background:

• The ataxia-telangiectasia and Rad3-related (ATR) kinase pathway is crucial for managing DNA replication stress in eukaryotes.
• ATR stabilizes replication forks, regulates DNA replication, and prevents mitotic entry with damaged DNA.
• ATR inhibitors are under clinical investigation for cancer treatment, necessitating a deeper understanding of ATR-dependent pathways.

Purpose of the Study:

• To genetically map cellular pathways dependent on ATR kinase function.
• To identify genes that, when mutated, confer hypersensitivity to ATR inhibitors.
• To provide a comprehensive gene set for understanding ATR biology and predicting therapeutic response.

Main Methods:

• Genome-scale CRISPR/Cas9 screening was employed to identify genes associated with hypersensitivity to ATR inhibitors.
• A consensus set of 117 genes was delineated through these screens.
• 14 genes from the set were validated, including novel modulators of ATR inhibitor response.

Main Results:

• A consensus set of 117 genes was identified, enriched in DNA replication, repair, and cell cycle regulation.
• Loss of POLE3/POLE4 proteins, DNA polymerase ε accessory subunits, resulted in significant hypersensitivity to ATR inhibition.
• Several previously undescribed genes modulating ATR inhibitor response were reported.

Conclusions:

• The identified 117-gene set is valuable for discovering genes regulating genome integrity and characterizing ATR-related biological processes.
• This research may reveal biomarkers for predicting patient response to ATR inhibitors in clinical settings.
• Understanding these genetic dependencies can refine ATR inhibitor-based cancer therapies.