biostudies-literatureUnknown52Roggero CMDespite widespread deregulation of CDK4/6 activity in non-small cell lung cancer (NSCLC), clinical trials with CDK4/6 inhibitor (CDK4/6i) as a monotherapy have shown poor antitumor activity. Preclinical studies indicate that CDK4/6i may collaborate by influencing DNA damage repair pathways during radiotherapy. Since PARP1 expression was also significantly upregulated in NSCLC, we analyzed the efficacy of combining PARP1 and CDK4/6 inhibition in NSCLC models. We found that CDK4/6is synergize with PARP1 inhibitors (PARPis) to inhibit the clonogenic growth of RB-proficient NSCLC models. This synergy correlates with increased accumulation of DNA damage, interrupted cell-cycle checkpoints, and enhanced apoptotic cell death. Mechanistically, we showed that CDK4/6is promote PARP1 protein degradatTranslational oncology102231https://www.ebi.ac.uk/biostudies/studies/S-EPMC11683282biostudies-literatureCDK4/6 inhibitors promote PARP1 degradation and synergize with PARP inhibitors in non-small cell lung cancer.PMC11683282Raj GVYin YMa SRoggero CMDevineni AGhosh ABBlatt EfalseCDK4/6 inhibitors promote PARP1 degradation and synergize with PARP inhibitors in non-small cell lung cancer.Despite widespread deregulation of CDK4/6 activity in non-small cell lung cancer (NSCLC), clinical trials with CDK4/6 inhibitor (CDK4/6i) as a monotherapy have shown poor antitumor activity. Preclinical studies indicate that CDK4/6i may collaborate by influencing DNA damage repair pathways during radiotherapy. Since PARP1 expression was also significantly upregulated in NSCLC, we analyzed the efficacy of combining PARP1 and CDK4/6 inhibition in NSCLC models. We found that CDK4/6is synergize with PARP1 inhibitors (PARPis) to inhibit the clonogenic growth of RB-proficient NSCLC models. This synergy correlates with increased accumulation of DNA damage, interrupted cell-cycle checkpoints, and enhanced apoptotic cell death. Mechanistically, we showed that CDK4/6is promote PARP1 protein degradat2024-01-01T00:00:00Z2024 Dec2025-04-04T08:11:47.662Z2025-04-04T08:11:47.662ZS-EPMC116832823966244910.1016/j.tranon.2024.102231