Targeting the DNA Damage Response Pathway as a Novel Therapeutic Strategy in Colorectal Cancer

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Recent advances in colorectal cancer (CRC) treatment include targeted therapies and immunotherapy, yet many advanced patients still have poor prognoses.
• DNA damage response (DDR) alterations are an emerging therapeutic target across various cancer types.
• PARP inhibitors are approved for cancers with BRCA1/2 mutations or homologous recombination repair deficiency (HRD).

Purpose of the Study:

• To review preclinical and clinical data on DDR inhibitors in colorectal cancer (CRC).
• To highlight the predictive role of DDR mutations in response to platinum-based chemotherapy.
• To explore the potential clinical utility of DDR inhibitors in CRC treatment.

Main Methods:

• Literature review of preclinical studies and clinical trials involving DDR inhibitors in CRC.
• Analysis of existing data on the prevalence and clinical impact of HRD in CRC.
• Examination of the predictive value of DDR mutations for chemotherapy response.

Main Results:

• Alterations in DDR genes, indicative of HRD, are found in 15-20% of CRCs, but their clinical role remains largely undefined.
• DDR mutations show predictive potential for response to platinum-based chemotherapy in CRC.
• Preclinical and clinical data suggest potential therapeutic opportunities with novel DDR inhibitors for CRC.

Conclusions:

• HRD is an emerging factor in CRC, present in a significant subset of patients.
• DDR inhibitors represent a promising therapeutic avenue for CRC, particularly for patients with specific DDR alterations.
• Further preclinical and clinical research is essential to fully elucidate the impact of DDR alterations and optimize the use of DDR inhibitors in CRC management.