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

Abstract

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.

The impact of a multispecialty operative team on colorectal cancer surgery: A retrospective study from a would-be medical center in Taiwan

“…Incidentally, in patients with metastatic CRC (mCRC) and complicated cases who had surgery performed by a single surgeon, those treated with targeted therapy had higher OS rates than those treated without targeted therapy. Therefore, targeted therapy should be performed first for mCRC, which is in line with the current treatment guidelines for mCRC, [17–21] giving priority to the treatment of the metastatic site rather than the primary site.…”

Update on Chemoresistance Mechanisms to First-Line Chemotherapy for Gallbladder Cancer and Potential Reversal Strategies

“…However, this mechanism of self-repair can drive cancer cells to develop resistance to chemotherapy drugs. Targeting DNA damage response pathways has been used as a therapeutic strategy for colorectal cancer, and DNA damage response inhibitors are being further evaluated in preclinical and clinical studies 50. Lovastatin can inhibit cholesterol biosynthesis in GBC and also increase the sensitivity of cancer cells to cisplatin by inhibiting the expression of CHK1, CHK2, and H2AX, during the DNA damage response 51.…”

Concurrent loss of MLH1, PMS2 and MSH6 immunoexpression in digestive system cancers indicating a widespread dysregulation in DNA repair processes

“…Considering this overlap of MMR and HRR and with the advent of drugs targeting DNA repair in clinical practice for other cancer entities, especially PARP-inhibitors for BRCA -mutated carcinomas ( 26 , 27 ), we proposed that our subgroup with a dysregulated MMR immunophenotype may be also a suitable cohort to search for additional defects in DNA repair processes. As novel therapies targeting other HRR pathway components than BRCA1/ 2 like ATM , ATR or CHEK1/2 are now under clinical investigation ( 28 , 29 ), working out subgroups likely to benefit from such drugs will be crucial.…”