Targeting the DNA damage response for cancer therapy.

Area of Science:

• Molecular Biology
• Oncology
• Pharmacology

Background:

• The DNA damage response (DDR) is crucial for maintaining genomic stability against DNA damage from internal and external sources.
• Cancer therapies like chemotherapy and radiotherapy induce DNA damage, but the DDR can act as a resistance mechanism.
• Targeting DDR pathways is a key strategy in cancer treatment.

Purpose of the Study:

• To review the development and clinical status of drugs targeting the DNA damage response (DDR).
• To highlight the potential of exploiting cancer-specific DDR defects as therapeutic vulnerabilities.
• To discuss the need for reliable biomarkers for personalized DDR-targeted cancer therapy.

Main Methods:

• Overview of the DNA damage response (DDR) system.
• Review of the rationale and development of DDR-inhibiting drugs.
• Summary of the clinical status of approved and investigational DDR-targeting agents.

Main Results:

• Inhibiting DDR to overcome resistance has not consistently improved therapeutic index.
• Exploiting cancer-specific DDR defects, such as homologous recombination deficiency (HRD), is a successful strategy.
• PARP inhibitors (PARPi) demonstrate selective killing of HRD cancer cells, with six currently approved.
• Other DDR-targeting drugs are in preclinical and clinical evaluation for monotherapy and combination treatments.

Conclusions:

• Targeting cancer-specific DDR defects represents a promising approach to selective tumor targeting.
• Reliable biomarkers are essential for identifying tumors suitable for DDR-targeted monotherapy.
• Potential toxicities of combination therapies targeting the DDR require careful consideration.