PARP1 impact on DNA repair of platinum adducts: preclinical and clinical read-outs.

摘要: Abstract Evaluation of DNA repair proteins might provide meaningful information in relation to prognosis and chemotherapy efficacy Non-Small Cell Lung Cancer (NSCLC) patients. The role Poly(ADP-Ribose) Polymerase (PARP) platinum adducts has not been firmly established. We used a functional test based on antibody recognition cisplatin intrastrand DNA. evaluated the effect PARP inhibition functionality panel cell lines treated by clinical-grade pharmacological inhibitor CEP8983 (a 4-methoxy-carbazole derivate) commercially available PJ34 (phenanthridinone). determined PARP1 protein expression whole tumor sections from International Adjuvant cancer Trial (IALT)-bio study tested 3-marker PARP1/MSH2/ERCC1 algorithm combining status with previously published data. Chemosensitivity NSCLC was correlated accumulation ( P =0.0004). Further, induced 1.7 2.3-fold increase adduct (24h) A549 line suggesting slow-down DNA-adduct capacity. In parallel, increased sensitivity treatment. patient samples, levels did influence survival or platinum-based post-operative global IALT-bio population (interaction =0.79). Among cases high all three markers (triple positive), untreated patients had prolonged median DFS 7.8 years, (HR=0.34, 95%CI [0.19–0.61], adjusted =0.0003) compared triple negative (1.4 years). Remarkably, positive suffered detrimental (4.9-year reduction DFS) cisplatin-based (HR=1.79, [1.01–3.17], =0.04, vs. control). Combinatorial sub-group analysis 3 further suggested that positivity constitute molecular context theranostic interest ERCC1 MSH2 NSCLC. conclusion, our data confirm is linked chemosensitivity, which inhibitors points PARP-dependent process. suggest biomarkers should be analyzed larger multiple pathway regulation.