Radiotherapy is an important component of current treatment options for colorectal cancer (CRC). It is either applied as neoadjuvant radiotherapy to improve local disease control in rectal cancers or for the treatment of localized metastatic lesions of CRC. DNA double-strand breaks (DSBs) are the major critical lesions contributing to ionizing radiation (IR)-induced cell death. However, CRC stem cells promote radioresistance and tumor cell survival through activating cell-cycle checkpoints to trigger the DNA damage response (DDR) and DNA repair after exposure to IR. A promising strategy to overcome radioresistance is to target the DDR and DNA repair pathways with drugs that inhibit activated cell-cycle checkpoint proteins, thereby improving the sensitivity of CRC cells to radiotherapy. In this review, we focus on the preclinical studies and advances in clinical trials of DNA-dependent protein kinase catalytic subunit (DNA-PKcs), ataxia telangiectasia mutated (ATM), ataxia telangiectasia and Rad3-related kinase (ATR), checkpoint kinase 1 (CHK1), checkpoint kinase 2 (CHK2), WEE1 and poly (ADP-ribose) polymerase 1 (PARP1) kinase inhibitors in CRC. Importantly, we also discuss the selective radiosensitization of CRC cells provided by synthetic lethality of these inhibitors and the potential for widening the therapeutic window by targeting the DDR and DNA repair pathways in combination with radiotherapy and immunotherapy.

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Background: Immune checkpoint inhibitors (ICIs) have made a significant breakthrough in the treatment of solid tumors; however, their use also generates unique immune-related adverse effects (irAEs). Here, we performed a systematic review and meta-analysis to assess the risk of immune-related liver dysfunction between in patients treated by programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors exclusively and chemotherapy.Methods: A comprehensive search of multiple databases identified eligible studies, including randomized controlled trials (RCTs) with PD-1/PD-L1 inhibitors exclusively and chemotherapy in patients with different solid tumors was carried out. The elevations of alanine aminotransferase (ALT) and aspartic aminotransferase (AST) were used to evaluate liver dysfunction. The relative risk (RR) and 95% confidence intervals (CI) were calculated and analyzed by Review Manager 5.3 and STATA version 12.0 statistical software.Results: After screening and eligibility assessment, a total of 5638 patients from 12 RCTs were included in our meta-analysis. In comparison with chemotherapy, patients treated with PD-1/PD-L1 inhibitors exclusively showed an increased incidence of all-grade ALT/AST elevations (ALT: RR, 1.52, 95% CI, 1.09–2.13; p = 0.01; AST: RR, 1.96, 95% CI, 1.37–2.81; p = 0.0002). Patients receiving PD-1 inhibitors showed the significantly higher risk of all-grade ALT/AST elevations incidence than those receiving chemotherapy (ALT: RR, 1.47; 95% CI, 1.05–2.07; p = 0.03; AST: RR, 1.90, 95% CI, 1.32–2.73; p = 0.0005). However, no significant difference was found between PD-L1 inhibitor and chemotherapy group. Moreover, for non-small cell lung cancer (NSCLC) and urothelial carcinoma (UC), patients treated with PD-1/PD-L1 inhibitors exclusively exhibited a significant higher risk of all-grade ALT elevation incidence (NSCLC: RR, 1.92; 95% CI, 1.23–3.02; p = 0.004; UC: RR, 3.36; 95% CI, 1.12–10.06, p = 0.03) and all-grade AST elevation incidence (NSCLC: RR, 2.37; 95% CI, 1.45–3.87, p = 0.0005; UC: RR, 4.47; 95% CI, 1.30–15.38, p = 0.02) than chemotherapy.Conclusions: The meta-analysis confirms that PD-1/PD-L1 inhibitors exclusive pose an increased risk of immune-related liver dysfunction than chemotherapy. PD-1/PD-L1 blockade in NSCLC and UC increase the risk of immune-related liver dysfunction, but not in melanoma (MM) and head-neck squamous cell carcinoma (HNSCC).