Genomic instability is a core characteristic of cancer, often stemming from defects in DNA damage response (DDR) or increased replication stress. DDR defects can lead to significant genetic alterations, including changes in gene copy numbers, gene rearrangements, and mutations, which accumulate over time and drive the clonal evolution of cancer cells. However, these vulnerabilities also present opportunities for targeted therapies that exploit DDR deficiencies, potentially improving treatment efficacy and patient outcomes. The development of PARP inhibitors like Olaparib has significantly improved the treatment of cancers with DDR defects (e.g., BRCA1 or BRCA2 mutations) based on synthetic lethality. This achievement has spurred further research into identifying additional therapeutic targets within the DDR pathway. Recent progress includes the development of inhibitors targeting other key DDR components such as DNA-PK, ATM, ATR, Chk1, Chk2, and Wee1 kinases. Current research is focused on optimizing these therapies by developing predictive biomarkers for treatment response, analyzing mechanisms of resistance (both intrinsic and acquired), and exploring the potential for combining DDR-targeted therapies with chemotherapy, radiotherapy, and immunotherapy. This article provides an overview of the latest advancements in targeted anti-tumor therapies based on DDR and their implications for future cancer treatment strategies.

The oncogenic role of circRNA in cancers including esophageal cancer (EC) has been well studied. However, whether and how circRNAs are involved in cancer cell metabolic processes remains largely unknown. Here, we reported that circRNA, circHIPK3, is highly expressed in ESCC cell lines and tissues. Knockdown of circHIPK3 significantly restrained cell proliferation, colony formation, migration, and invasion in vitro and inhibited tumor growth in vivo. Mechanistically, circHIPK3 was found to act as a ceRNA by sponging miR-637 to regulate FASN expression and fatty acid metabolism in ESCC cells. Anti-sense oligonucleotide (ASO) targeting circHIPK3 substantially inhibited ESCC both in vitro and in vivo. Therefore, these results uncover a modulatory axis constituting of circHIPK3/miR-637/FASN may be a potential biomarker and therapeutic target for ESCC in the clinic.

Background: Sarcopenia is closely associated with surgical complications in patients with certain cancers. In this study we assessed the relationship between sarcopenia and postoperative complications in patients with oesophageal squamous cell carcinoma. Methods: We retrospectively analysed of patients who underwent thoracoscopic combined with laparoscopic radical resection of oesophageal cancer. Preoperative computed tomography to evaluate skeletal muscle mass to diagnose sarcopenia and to evaluate associations with age, body mass index (BMI), lung function and postoperative complications. Results: Among 141 patients, 73 presented with sarcopenia (sarcopenia group) and 68 did not (non-sarcopenia group). The mean skeletal muscle index in all patients was 49.5±9.0 cm²/m²; median, 49.3 cm²/m². The sarcopenia group included a higher proportion of men (P=0.039) and had a lower BMI than the non-sarcopenia group (P=0.001). There were no significant differences in any other clinical and pathological features. The incidences of postoperative complications in the sarcopenia and non-sarcopenia groups were 63.0% and 36.8%, respectively (P=0.002). The incidences of pulmonary infections and postoperative pleural effusions were 28.8% vs. 11.8% (P=0.011) and 38.4% vs. 20.6% (P=0.020) in the sarcopenia and non-sarcopenia groups, respectively. The incidences of other complications were not significantly different between the two groups. Univariate and multivariate analyses of pulmonary infection-related clinical factors revealed that sarcopenia and forced expiratory volume in the first second as a percent of forced vital capacity (FEV1.0%) were independent risk factors for pulmonary infection after minimally invasive surgery. Conclusions: Preoperative sarcopenia is an independent risk factor for pulmonary infection after minimally invasive oesophagectomy (MIE). Evaluation of preoperative sarcopenia will thus help to prevent postoperative complications.