A first-in-class polymerase theta inhibitor selectively targets homologous-recombination-deficient tumors
Menée à l'aide de modèles murins de tumeur de l'ovaire ou du sein avec déficience du système de réparation de l'ADN par recombinaison homologue et menée à l'aide de xénogreffes dérivées de tumeurs de patients, cette étude met en évidence l'intérêt thérapeutique de la novobiocine, un antibiotique inhibant spécifiquement l'ADN polymérase thêta
DNA polymerase theta (POLθ or POLQ) is synthetic lethal with homologous recombination (HR) deficiency and is thus a candidate target for HR-deficient cancers. Through high-throughput small-molecule screens, we identified the antibiotic novobiocin (NVB) as a specific POLθ inhibitor that selectively kills HR-deficient tumor cells in vitro and in vivo. NVB directly binds to the POLθ ATPase domain, inhibits its ATPase activity and phenocopies POLθ depletion. NVB kills HR-deficient breast and ovarian tumors in genetically engineered mouse models and xenograft and patient-derived xenograft models. Increased POLθ levels predict NVB sensitivity, and HR-deficient tumor cells with acquired resistance to poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are sensitive to NVB in vitro and in vivo. Mechanistically, NVB-mediated cell death in PARPi-resistant cells arises from increased double-strand break end resection, leading to accumulation of single-stranded DNA intermediates and nonfunctional foci of the recombinase RAD51. Our results demonstrate that NVB may be useful alone or in combination with PARPi for treating HR-deficient tumors, including those with acquired PARPi resistance.