Targeting ATR as Cancer Therapy: A new era for synthetic lethality and synergistic combinations?

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• The DNA damage response (DDR) is crucial for detecting and repairing DNA damage, involving cell cycle checkpoints.
• Ataxia telangiectasia and Rad3-related (ATR) protein kinase is central to DDR, sensing replication stress (RS) and signaling to cell cycle checkpoints.
• Cancer cells often exhibit increased RS due to checkpoint deficiencies and oncogene activation, increasing reliance on ATR-dependent checkpoints.

Purpose of the Study:

• To review preclinical data on ATR inhibitors as monotherapy and in combination treatments.
• To discuss current clinical trial data for ATR inhibitors.
• To identify challenges and potential biomarkers for patient selection in ATR inhibitor therapy.

Main Methods:

• Summary of preclinical data supporting ATR inhibitor efficacy.
• Review of clinical trial outcomes for ATR inhibitors.
• Discussion of challenges in clinical translation and biomarker development.

Main Results:

• Preclinical data support ATR inhibitors as monotherapy and in combination with chemotherapy, radiotherapy, and PARP inhibitors.
• Several ATR inhibitors are in clinical development, showing promise in oncology.
• Biomarker identification is crucial for patient selection and optimizing ATR inhibitor therapy.

Conclusions:

• ATR inhibitors represent a significant therapeutic strategy in oncology, particularly for cancers with high replication stress.
• Clinical development of ATR inhibitors is ongoing, with ongoing efforts to overcome challenges and identify predictive biomarkers.
• Combination strategies and targeted patient selection are key to maximizing the efficacy of ATR inhibitors.