Targeting the DNA Damage Response and DNA Repair Pathways to Enhance Radiosensitivity in Colorectal Cancer.

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.

Enhancer of zeste homolog 2 contributes to apoptosis by inactivating janus kinase 2/ signal transducer and activator of transcription signaling in inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease (IBD) is a prevalent worldwide health problem featured by relapsing, chronic gastrointestinal inflammation. Enhancer of zeste homolog 2 (EZH2) is a critical epigenetic regulator in different pathological models, such as cancer and inflammation. However, the role of EZH2 in the IBD development is still obscure. AIM: To explore the effect of EZH2 on IBD progression and the underlying mechanism. METHODS: The IBD mouse model was conducted by adding dextran sodium sulfate (DSS), and the effect of EZH2 on DSS-induced colitis was assessed in the model. The function of EZH2 in regulating apoptosis and permeability was evaluated by Annexin V-FITC Apoptosis Detection Kit, transepithelial electrical resistance analysis, and Western blot analysis of related markers, including Zona occludens 1, claudin-5, and occludin, in NCM460 and fetal human colon (FHC) cells. The mechanical investigation was performed by quantitative reverse transcription-polymerase chain reaction, Western blot analysis, and chromatin immunoprecipitation assays. RESULTS: The colon length was inhibited in the DSS-treated mice and was enhanced by the EZH2 depletion in the system. DSS treatment caused a decreased histological score in the mice, which was reversed by EZH2 depletion. The inflammatory cytokines, such as tumor necrosis factor-α, interleukin-6, and interleukin-1ß, were induced in the DSS-treated mice, in which the depletion of EZH2 could reverse this effect. Moreover, the tumor necrosis factor-α treatment induced the apoptosis of NCM460 and FHC cells, in which EZH2 depletion could reverse this effect in the cells. Moreover, the depletion of EZH2 attenuated permeability of colonic epithelial cells. Mechanically, the depletion of EZH2 or EZH2 inhibitor GSK343 was able to enhance the expression and the phosphorylation of janus kinase 2 (JK2) and signal transducer and activator of transcription in the NCM460 and FHC cells. Specifically, EZH2 inactivated JAK2 expression by regulating histone H3K27me3. JAK2 inhibitor TG101348 was able to reverse EZH2 knockdown-mediated colonic epithelial cell permeability and apoptosis. CONCLUSION: Thus, we concluded that EZH2 contributed to apoptosis and inflammatory response by inactivating JAK2/ signal transducer and activator of transcription signaling in IBD. EZH2 may be applied as a potential target for IBD therapy.

Oral Tongue Cancer in a Patient with Fanconi Anemia: A Case Report and Literature Review.

PURPOSE: Fanconi anemia (FA) is a rare genetic disorder characterized by congenital anomalies, progressive bone marrow failure and high susceptibility to solid tumors, especially head and neck squamous cell carcinoma (HNSCC). Management of FA patients with head and neck cancer is a challenge due to increased risk of surgery, poor tolerance of chemotherapy, and severe myelotoxicity of radiotherapy. PATIENTS AND METHODS: We present a case of a 33-year-old man with carcinoma of oral tongue (T1N2M0), who experienced prolonged and profound bone marrow failure as a consequence of concurrent cisplatin/radiation. The young patient who developed HNSCC without risk factors, the myelotoxicity after exposure to platinum-based agent cisplatin and the further evaluation of phenotypic characteristics raised suspicion of FA. Whole exome sequencing performed for the patient and parents ultimately established the diagnosis of FA. RESULTS: Genetic testing in 23 FANC genes revealed two novel heterozygous mutations, c.367C>T and c.3971_3972delCGinsTT in FANCA gene of the patient, which were inherited from his father and mother, respectively. Radiotherapy with reduced dose has successfully alleviated the symptoms of tumor invasion and progression, and the radiation-related side effects were acceptable. Unfortunately, the patient eventually died of locoregional disease progression. CONCLUSION: This case highlights the importance of considering the diagnosis of FA in young patients who develop HNSCC in the absence of risk factors, thus permitting more effective oncological treatment strategies and improved outcomes. In conclusion, any decision on different modalities of management in such patients should be based on a balance between locoregional control and therapeutic toxicity.

Single nucleotide polymorphisms within NFKBIA are associated with nasopharyngeal carcinoma susceptibility in Chinese Han population.

Genes involved in latent membrane protein 1 (LMP1) signaling pathways have been suggested to play an important role in nasopharyngeal carcinogenesis. We investigated potentially functional genetic variants associated with the risk of nasopharyngeal carcinoma (NPC) in genes involved in the LMP1 signaling pathway. Altogether, 73 single nucleotide polymorphisms (SNPs) with MAF ≥ 10% were located within the regions of interest of the four genes TRAF3, NFKBIA, CHUK and MAP2K4. From these, 10 SNPs were selected for genotyping based on LD (r2 ≥ 0.80) in a hospital-based case-control study of 332 NPC cases and 585 healthy controls from the Chinese Han population. Minor allele carriers of the promoter SNP rs2233409 in NFKBIA, had an increased risk of NPC (AA vs GG: OR 7.14, 95%CI, 1.08-34.18, P = 0.04, dominant model). Based on the results, we concluded that rs2233409 polymorphism in NFKBIA may be moderately associated with the risk of NPC. Further studies with larger independent samples and functional analysis are needed to verify our results.

The Relative Risk of Immune-Related Liver Dysfunction of PD-1/PD-L1 Inhibitors Versus Chemotherapy in Solid Tumors: A Meta-Analysis of Randomized Controlled Trials.

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).