ATR inhibition augments the efficacy of lurbinectedin in small-cell lung cancer.

ABSTRACT: Small-cell lung cancer (SCLC) is the most lethal type of lung cancer. Specifically, MYC-driven non-neuroendocrine SCLC is particularly resistant to standard therapies. Lurbinectedin was recently approved for the treatment of relapsed SCLC, but combinatorial approaches are needed to increase the depth and duration of responses to lurbinectedin. Using high-throughput screens, we found inhibitors of ataxia telangiectasia mutated and rad3 related (ATR) as the most effective agents for augmenting lurbinectedin efficacy. First-in-class ATR inhibitor berzosertib synergized with lurbinectedin in multiple SCLC cell lines, organoid, and in vivo models. Mechanistically, ATR inhibition abrogated S-phase arrest induced by lurbinectedin and forced cell cycle progression causing mitotic catastrophe and c

SUBMITTER: Schultz CW 

PROVIDER: S-EPMC10405061 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature