A first-in-class polymerase theta inhibitor selectively targets homologous-recombination-deficient tumors

D'Andrea and colleagues identify the antibiotic novobiocin as a specific POLQ inhibitor with preclinical activity in homologous-recombination-deficient breast and ovarian tumors in vivo, including these with acquired PARP inhibitor resistance. DNA polymerase theta (POL theta 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 POL theta inhibitor that selectively kills HR-deficient tumor cells in vitro and in vivo. NVB directly binds to the POL theta ATPase domain, inhibits its ATPase activity and phenocopies POL theta depletion. NVB kills HR-deficient breast and ovarian tumors in genetically engineered mouse models and xenograft and patient-derived xenograft models. Increased POL theta 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.

Automated summary

The antibiotic novobiocin has been identified as a specific POLQ inhibitor with preclinical activity in homologous-recombination-deficient breast and ovarian tumors, including those with acquired PARP inhibitor resistance. This study suggests that novobiocin may be useful alone or in combination with PARP inhibitors for treating HR-deficient tumors.