Drugging the DNA damage response in the clinic: going beyond PARP

Area of Science:

• Oncology
• Pharmacology
• Genetics

Background:

• Targeting the DNA damage response (DDR) is a key strategy in cancer therapy.
• PARP inhibitors are established DDR-targeting agents, but novel inhibitors are emerging.
• Understanding DDR pathways is crucial for developing new cancer treatments.

Purpose of the Study:

• To review the clinical relevance of novel DNA damage response (DDR) inhibitors beyond PARP inhibitors.
• To highlight emerging DDR targets, patient selection biomarkers, and combination strategies.
• To summarize preclinical and clinical data on next-generation DDR inhibitors.

Main Methods:

• Comprehensive literature search of PubMed and ClinicalTrials.gov up to May 2025.
• Review of preclinical and clinical data on specific DDR inhibitors (e.g., ATR, ATM, WEE1).
• Analysis of mechanistic rationale, clinical activity, safety, and combination strategies.

Main Results:

• Next-generation DDR inhibitors targeting ATR, ATM, WEE1, and others show clinical activity.
• Combination strategies with chemotherapy, immunotherapy, and radiotherapy are being explored.
• Challenges include resistance, toxicity, and the need for predictive biomarkers.

Conclusions:

• DDR-targeting agents are promising, especially with biomarker guidance and combination therapies.
• Future development requires biomarker-driven design and toxicity mitigation.
• Expanding use to non-canonical tumor types may maximize clinical impact.