ATR (Ataxia telangiectasia and Rad3-related protein)

This study evaluates the expression of DNA damage response genes-ETAA1, TOPBP1, and ATR-in patients with Duchenne Muscular Dystrophy (DMD). The results demonstrate that DMD patients have much greater gene expression levels and oxidative stress indicators than healthy controls. These genes show a favorable correlation with clinical severity indicators such as CKMM, CPK, and LDH. Combining the three markers improves diagnostic sensitivity and specificity, indicating their potential as a multi-gene biomarker panel. The findings shed fresh light on DMD etiology by correlating genomic instability to disease progression and identifying possible molecular targets for early detection and future treatment approaches.

We provide a detailed analysis of the structure-activity relationships (SAR) of leading clinical candidates, including berzosertib, ceralasertib, and elimusertib, focusing on strategic chemical modifications such as scaffold hopping and sulfoximine substitution to optimize selectivity and druggability. Critical challenges, specifically dose-limiting hematological toxicities and acquired resistance, are analyzed alongside the search for robust predictive biomarkers. By synthesizing current pharmacological and clinical data, this work outlines the trajectory for next-generation ATR-targeted precision medicine.

Additionally, the ATRi induced reactivation of CD8+ T cells was linked to spatial interactions with replication stress positive tumor cells. Thus, our iPDC platform presents as a representative high-throughput ex vivo model to advance precision oncology in HGSC uncovering ATRi-immunotherapy combination as a potentially effective therapeutic option for clinical translation.

Camonsertib and low-dose gemcitabine demonstrated preliminary clinical activity, but due to challenging tolerability further evaluation is warranted to identify the optimal dosing regimen and subset of patients who may benefit most from this combination.

Finally, TOP1α and TOP3β differentially regulate the formation of R-loops, which are critical for viral replication. These findings demonstrate the differential roles of type I topoisomerases in HPV pathogenesis.

Their coregulation analysis across CHK1 substrates, kinase regulators, and protein interactions uncovered connectivity between CHK1 phosphosites and DDR regulators. Collectively, our phosphosite-concordance approach reported here provides a regulatory map of CHK1 phosphorylation patterns, uncovering unexplored regulatory layers, and highlights new opportunities to explore mechanistic insights into CHK1 phosphoregulation as a target for therapeutic interventions in cancer.

Further studies are required to confirm the role of ATRIP in breast cancer susceptibility, refine risk assessment, and evaluate potential personalized therapeutic strategies. In the interim, genetic counseling for ATRIP mutation carriers should proceed with caution, given current limitations in clinical interpretation.

Through targeting these TOPBP1-nucleated molecular machineries, auranofin leads to an accumulation of replication defects by impairing ATR activation and attenuating replication protein A loading on perturbed replication forks, and it shows significant anti-breast tumor activity in combination with a PARP inhibitor. This study provides mechanistic insights into how auranofin challenges replication integrity and expands the application of this FDA-approved drug in breast tumor intervention.

Ceralasertib monotherapy was generally well tolerated in Japanese patients with advanced solid tumors. The small number of patients enrolled prevents definitive conclusions on the efficacy of ceralasertib monotherapy to be made.

Sirtinol was detected in the brains of sirtinol-treated mice, suggesting blood brain barrier penetrance. Conclusions : Based on our results, sirtinol shows promise as a selective, redox-modulating therapeutic for DIPG that enhances oxidative stress and interferes with DNA repair.

The challenges that must be addressed to see the true potential of these agents are discussed. Finally, we consider future directions and the necessity for integration of biomarkers and genomic profiling in DDR inhibitor clinical trials to optimally identify patients with tumours genetically vulnerable, and so crucially, take advantage of the selective therapeutic opportunity provided by DDR inhibition.

This resistance is suppressed by exogenously transfected miR-181d. These findings suggest that microRNA regulates intratumoral heterogeneity by modulating the transcriptional variability of key DNA repair enzymes, providing a compelling rationale for miRNA delivery as a platform for glioblastoma therapy.