CDK4/6 inhibitors promote PARP1 degradation and synergize with PARP inhibitors in non-small cell lung cancer.

ABSTRACT: 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 degradat

SUBMITTER: Roggero CM 

PROVIDER: S-EPMC11683282 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature