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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.

IntroductionLung cancer, with the highest global mortality rate among cancers, presents a grim prognosis, often diagnosed at an advanced stage in nearly 70% of cases. Recent research has unveiled a novel mechanism of cell death termed disulfidptosis, which is facilitated by glucose scarcity and the protein SLC7A11.MethodsUtilizing the least absolute shrinkage and selection operator (LASSO) regression analysis combined with Cox regression analysis, we constructed a prognostic model focusing on disulfidptosis-related genes. Nomograms, correlation analyses, and enrichment analyses were employed to assess the significance of this model. Among the genes incorporated into the model, CHRNA5 was selected for further investigation regarding its role in LUAD cells. Biological functions of CHRNA5 were assessed using EdU, transwell, and CCK-8 assays.ResultsThe efficacy of the model was validated through internal testing and an external validation set, with further evaluation of its robustness and clinical applicability using a nomogram. Subsequent correlation analyses revealed associations between the risk score and infiltration of various cancer types, as well as oncogene expression. Enrichment analysis also identified associations between the risk score and pivotal biological processes and KEGG pathways. Our findings underscore the significant impact of CHRNA5 on LUAD cell proliferation, migration, and disulfidptosis.ConclusionThis study successfully developed and validated a robust prognostic model centered on disulfidptosis-related genes, providing a foundation for predicting prognosis in LUAD patients.

ObjectiveAnatomical segmentectomy has been proven to be a viable surgical treatment for small-size peripheral lung nodules. Three-dimensional (3D) reconstruction computed tomography (CT) has been proposed as an effective approach to overcome the challenges of encountering pulmonary anatomical variations when performing segmentectomy. Therefore, to further investigate the usefulness of preoperative 3D reconstruction CT in segmentectomy, we will conduct this prospective, multicenter randomized controlled DRIVATS study to compare the use of 3D reconstruction CT with standard chest CT in video-assisted segmentectomy (ClinicalTrials.gov ID: NCT04004494).MethodsThis study began in July 2019 and a total of 190 patients will be accrued from three clinical centers within 4 years. The main inclusion criteria are patients with a single peripheral nodule 0.8–2 cm with at least one of the following requirements: (i) histology of adenocarcinoma in situ; (ii) nodule has ≥50% ground-glass appearance on CT; (iii) radiologic surveillance confirms a long doubling time (≥400 days). Surgical procedures include segmental resection of the lesion and mediastinal lymph node sampling (subsegmental resection or combined subsegmental resection will not be included in this study). The primary endpoint is operative time. The secondary endpoints include incidence of change of surgical plan, intraoperative blood loss, conversion rate, operative accident event, incidence of postoperative complications, postoperative hospital stay, length of hospitalization, duration of chest tube placement, postoperative 30-day mortality, dissection of lymph nodes, overall survival, disease-free survival, preoperative lung function, and postoperative lung function.DiscussionThis multicenter DRIVATS study aims to verify the usefulness of preoperative 3D reconstruction CT compared with standard chest CT in segmentectomy. If successfully completed, this multicenter prospective study will provide a higher level of evidence for the use of 3D reconstruction CT in segmentectomy.

Background: Brain metastasis (BM) frequently occurs in HER2-positive breast cancer (BC) patients, but the risk factors of BM in this type of patients are still unknown. Our study aims to assess the risk factors of BM and prognostic analysis in HER2-positive BC patients. Methods: Univariate analysis used t-test, chi-square test, and Fisher's exact test to find out the risk factors for BM, and multivariable analysis was done with stepwise logistic regression analysis. Prognostic data analysis was estimated by the Kaplan-Meier method. Results: A total of 228 HER2-positive BC patients were included, of whom 214 patients were postoperative metastatic patients and 14 patients were de novo stage IV patients. Through comparing the stratified variables between 51 postoperative metastatic patients with BM and 163 postoperative metastatic patients without BM, the multivariate analysis showed that age =40 years (OR 2.321, 95% CI: 1.089 to 4.948) and first metastatic site with lung metastasis (OR 2.168, 95% CI: 1.099 to 4.274) were independent risk factors for BM in HER2-positive BC patients. Prognostic data of all 65 HER2-positive BC patients with BM showed that the time from the diagnosis of BC to the development of breast cancer brain metastasis (BCBM) was 36.3 months (95% CI: 30.0 to 42.1 months). The time from the diagnosis of first recurrence and metastasis stage to the diagnosis of BCBM was 11.35 months (95% CI: 7.1 to 18.4 months). The time from the diagnosis of BCBM to the time of follow-up was 24.1 months (95% CI: 13.9 to 37.5 months). Up until the time of follow-up data, a total of 38 patients had died, and the time from the diagnosis of BM of these 38 patients to death was 11.0 months (95% CI: 9.0 to 20.4 months). Conclusion: The prognosis of HER2-positive BC patients with BM was poor due to the lack of effective treatments for BM. Age =40 years and first metastatic site with lung metastasis were the independent risk factors for BM in HER2-positive BC patients. Future research about pre-emptive medical interventions may help to improve the prognosis of HER2-positive BC patients with high risk to develop BM. [ABSTRACT FROM AUTHOR]