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

Simple Summary Defective DNA damage response (DDR) is a hallmark of cancer leading to genomic instability. Up to 15-20% of colorectal cancers carry alterations in DDR. However, the role of DDR alterations as a prognostic factor and as a therapeutic target must be elucidated. To date, disappointing results have been obtained in different clinical trials mainly due to poor molecular selection of patients. Several challenges must be overcome before these compounds may have an impact on colorectal cancer. For instance, although some preclinical evidence showed the vulnerability of a subset of CRCs to PARP inhibitors, no specific clinical or molecular biomarkers have been validated to select patients. Moreover, different DDR alterations may not equally confer platinum sensitivity in CRC patients. Further efforts are needed in both preclinical and clinical settings to exploit DDR alterations as therapeutic targets and to eventually discover PARP or other DDR inhibitors (e.g., Wee1) with clinical benefit on colorectal cancer patients. Major advances have been made in CRC treatment in recent years, especially in molecularly driven therapies and immunotherapy. Despite this, a large number of advanced colorectal cancer patients do not benefit from these treatments and their prognosis remains poor. The landscape of DNA damage response (DDR) alterations is emerging as a novel target for treatment in different cancer types. PARP inhibitors have been approved for the treatment of ovarian, breast, pancreatic, and prostate cancers carrying deleterious BRCA1/2 pathogenic variants or homologous recombination repair (HRR) deficiency (HRD). Recent research reported on the emerging role of HRD in CRC and showed that alterations in these genes, either germline or somatic, are carried by up to 15-20% of CRCs. However, the role of HRD is still widely unknown, and few data about their clinical impact are available, especially in CRC patients. In this review, we report preclinical and clinical data currently available on DDR inhibitors in CRC. We also emphasize the predictive role of DDR mutations in response to platinum-based chemotherapy and the potential clinical role of DDR inhibitors. More preclinical and clinical trials are required to better understand the impact of DDR alterations in CRC patients and the therapeutic opportunities with novel DDR inhibitors.