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 are 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

SUBMITTER: Dr. Christopher, William Schultz 

PROVIDER: S-SCDT-10_15252-EMMM_202217313 | biostudies-other |

REPOSITORIES: biostudies-other