Targeting the DNA Damage Response Pathways and Replication Stress in Colorectal Cancer

Area of Science:

• Oncology
• Cancer Genomics
• Drug Discovery

Background:

• Genomic instability is a key feature of cancer.
• Targeting DNA damage response (DDR) pathways is a promising therapeutic strategy for solid tumors.
• The efficacy of DDR inhibition in colorectal cancer remains underexplored.

Purpose of the Study:

• To investigate the effectiveness of targeting DDR pathways in colorectal cancer models.
• To identify biomarkers for response and resistance to ATR inhibitors (ATRi) in colorectal cancer.

Main Methods:

• Screened 112 metastatic colorectal cancer cell models with ATM, ATR, CHK1, WEE1, and DNA-PK inhibitors.
• Focused on ATR inhibitors and analyzed sensitive/resistant models for biomarkers.
• Utilized organoids derived from patients with metastatic colorectal cancer.

Main Results:

• Approximately 30% of colorectal cancers, including KRAS/BRAF-mutated types, responded to at least one DDR inhibitor.
• ATRi-sensitive cells showed reduced basal phospho-RPA32 foci; resistant cells had increased RAD51 foci upon replication stress.
• Lack of ATM/RAD51C expression and specific mutational signatures correlated with ATRi sensitivity.

Conclusions:

• A subset of colorectal cancers refractory to existing treatments may benefit from DDR and replication stress inhibitors.
• A composite biomarker including phospho-RPA32, RAD51 foci, ATM/RAD51C expression, and mutational signatures can predict ATRi response.