Chemo-Phosphoproteomic Profiling with ATR Inhibitors Berzosertib and Gartisertib Uncovers New Biomarkers and DNA...

Area of Science:

• Molecular Biology
• Cancer Research
• Biochemistry

Background:

• The ATR kinase is crucial for cellular response to DNA damage and replication stress, making it a key target for anti-cancer therapies.
• ATR inhibitors (ATRi) like berzosertib and gartisertib are under clinical investigation for solid tumors, often combined with genotoxic agents.

Purpose of the Study:

• To identify novel, highly sensitive biomarkers for ATR inhibitors (ATRi) using quantitative phospho-proteomic screening.
• To discover new proteins involved in genome maintenance and DNA damage response pathways regulated by ATR.

Main Methods:

• Quantitative phospho-proteomic screening using mass spectrometry to analyze ATR-dependent phosphorylation events.
• Secondary screening to assess the recruitment of candidate proteins to DNA damage sites.

Main Results:

• Identified novel ATR-dependent phosphorylation events, categorizing them into potential next-generation ATR biomarkers, known genome maintenance proteins regulated by ATR, and novel proteins with unclear roles.
• Demonstrated that SCAF1, a novel protein, is recruited to DNA damage sites in a phospho-dependent manner, requiring PARP activity and RNAPII interaction.
• Showed that SCAF1 deficiency partially rescues RAD51 loading in BRCA1-deficient cells, suggesting a role in genome maintenance.

Conclusions:

• The study presents potential new biomarkers for ATR inhibitors, aiding in patient selection and treatment monitoring.
• Discovered novel genome maintenance factors, including SCAF1, which could represent new therapeutic targets or contribute to understanding cancer progression.