The DNA damage response (DDR) system is a complicated network of signaling pathways that detects and repairs DNA damage or induces apoptosis. Critical regulators of the DDR network include the DNA damage kinases ataxia telangiectasia mutated Rad3-related kinase (ATR) and ataxia-telangiectasia mutated (ATM). The ATR pathway coordinates processes such as replication stress response, stabilization of replication forks, cell cycle arrest, and DNA repair. ATR inhibition disrupts these functions, causing a reduction of DNA repair, accumulation of DNA damage, replication fork collapse, inappropriate mitotic entry, and mitotic catastrophe. Recent data have shown that the inhibition of ATR can lead to synthetic lethality in ATM-deficient malignancies. In addition, ATR inhibition plays a significant role in the activation of the immune system by increasing the tumor mutational burden and neoantigen load as well as by triggering the accumulation of cytosolic DNA and subsequently inducing the cGAS-STING pathway and the type I IFN response. Taken together, we review stimulating data showing that ATR kinase inhibition can alter the DDR network, the immune system, and their interplay and, therefore, potentially provide a novel strategy to improve the efficacy of antitumor therapy, using ATR inhibitors as monotherapy or in combination with genotoxic drugs and/or immunomodulators.

The DNA damage response (DDR) system is a complicated network of signaling pathways that detects and repairs DNA damage or induces apoptosis. Critical regulators of the DDR network include the DNA damage kinases ataxia telangiectasia mutated Rad3-related kinase (ATR) and ataxia-telangiectasia mutated (ATM). The ATR pathway coordinates processes such as replication stress response, stabilization of replication forks, cell cycle arrest, and DNA repair. ATR inhibition disrupts these functions, causing reduction of DNA repair, accumulation of DNA damage, replication fork collapse, inappropriate mitotic entry and mitotic catastrophe. Recent data have shown that the inhibition of ATR can lead to synthetic lethality in ATM-deficient malignancies. In addition, ATR inhibition plays a significant role in the activation of the immune system by increasing the tumor mutational burden and neoantigen load as well as by triggering the accumulation of cytosolic DNA and subsequently inducing the cGAS-STING pathway and the type I IFN response. Taken together, we review stimulating data showing that ATR kinase inhibition can alter the DDR network, the immune system and their interplay and therefore potentially provide a novel strategy to improve the efficacy of antitumor therapy, using ATR inhibitors as monotherapy or in combination with genotoxic drugs and/or immunomodulators.

Simple Summary: DNA damage response (DDR) is a multi-factor network that is responsible for the removal of DNA lesions, thus enabling cells to function normally. An imbalance between the generation of reactive oxygen species and their removal by defense mechanisms is known as oxidative stress. Previous studies demonstrated that deregulation of the DDR network and redox imbalance are implicated in the onset and progression of several diseases, including cancer, as well as in the outcome of chemotherapy. In this study, we found that DDR-associated parameters and the intracellular redox status display significant differences among lung cancer patients at baseline and correlate with the clinical responses to subsequent platinum-based therapy. The exploitation of these results might lead to the identification of new therapeutic targets, the design of effective and sensitive biomarkers and the development of new therapeutic regimens for the treatment of this devastating malignancy.

Background: A substantial proportion of patients with non-small cell lung cancer (NSCLC) derive limited clinical benefit from immunotherapy. Monitoring of peripheral blood immune markers (PBIMs) may emerge as a useful tool to predict treatment outcomes with immune checkpoint inhibitors (ICIs). Patients/Methods: We prospectively measured several PBIMs in a PD-L1 high (TPS ≥ 50%) NSCLC cohort of patients treated with first-line pembrolizumab monotherapy. Kinetics over the first year of treatment were assessed at baseline (T0) and at 21 days (T1), 3 months (T2), 6 months (T3) and at 1 year (T4) post-treatment initiation. Associations with clinical outcomes were explored after a 2-year follow-up period. Results: In total, 31 patients with PD-L1 high locally advanced or metastatic NSCLC were prospectively enrolled. Over the first year of treatment, levels of CRP, IL-17α, IL-6, and IL-8 were significantly decreased. Early kinetics analysis showed significant decrease in total leukocytes, neutrophils, CRP, and MIP-3α/CCL20, as well as significant transient elevation of ITAC/CXCL11, IL-1β, IL-7, and TNFα, during the first 3 months of treatment. Early percent changes (Δ% at T1 and at T2) of ‘low’ vs. ‘high’ pretreatment levels showed significant differences for LDH, ITAC/CXCL11, GM-CSF, MIP-1α/CCL3, IL-2, IL-4, IL-5, and sPD-L1. Longitudinal analysis, stratified per responders and for pre-progression fluctuations, did not reveal significant findings. Among markers with acceptable discriminative performance, higher baseline CRP, complement C4, and IL-6 levels were associated with poorer clinical outcomes. In multivariable analysis, only C4 retained independent prognostic significance; however, integration of these PBIMs into composite indices improved prognostic performance. Conclusions: In this prospective study, longitudinal monitoring of PBIMs provided descriptive insights into immune and inflammatory dynamics during pembrolizumab treatment; however, no significant associations were observed between in-treatment biomarker kinetics and clinical outcomes. In exploratory analyses, baseline CRP, complement C4, and IL-6 levels were associated with clinical outcomes, and their integration into composite indices improved prognostic performance. These findings suggest that specific baseline PBIMs may carry prognostic relevance, while the role of in-treatment monitoring remains to be further clarified in larger prospective studies.

Background: Lung cancer (LC) remains the leading cause of cancer-related mortality worldwide. Soluble receptor for advanced glycation end products (sRAGE) has emerged as a candidate biomarker in metabolic, inflammatory, and malignant diseases, although its prognostic significance in LC remains uncertain. Methods: Serum sRAGE levels were prospectively measured at baseline and prior to the second cycle of treatment in patients with non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). Associations of sRAGE with overall survival (OS), progression-free survival (PFS), clinical features, and other biomarkers were analyzed. Results: In total, 42 patients were enrolled in this study. sRAGE was detected in 16 patients (38.1%) at baseline and in 15 patients (37.5%) after the first cycle of treatment. Pre-treatment sRAGE levels were strongly correlated with post-treatment levels (Pearson’s r = 0.78; 95% CI, 0.61–0.88; p = 4.1 × 10⁻⁹) and moderately correlated with PD-L1 tumor proportion score in NSCLC patients (Spearman’s ρ = 0.4, p = 0.049). Pre-treatment sRAGE levels tended to be higher in patients with indeterminate/high risk of liver fibrosis compared to patients with low risk (Wilcoxon rank-sum test, p = 0.041). Post-treatment change in sRAGE levels was correlated with whole blood cell count-derived inflammatory markers. A preliminary association between decreased sRAGE and overall survival in SCLC patients was observed. Conclusions: Serum sRAGE shows potential as a blood-based biomarker reflecting metabolic, immune, and inflammatory status in lung cancer, warranting further investigation to clarify its prognostic and therapeutic relevance.