Journal Article

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

Blagg, Brian S. J., Zhou, Jia, Färkkilä, Anniina, Syed, Aleem, Ceccaldi, Raphael, Yücel, Hatice, Shapiro, Geoffrey I., Davis, Rachel E., Kochupurakkal, Bose, D’Andrea, Alan D., Pantelidou, Constantia, Tainer, John A., Gelot, Camille, Li, Adam

2021

Overview

DNA polymerase theta (POLθ) is synthetic lethal with Homologous Recombination (HR) deficiency and 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 and . 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 GEMM, xenograft and PDX models. Increased POLθ levels predict NVB sensitivity, and BRCA-deficient tumor cells with acquired resistance to PARP inhibitors (PARPi) are sensitive to NVB and Mechanistically, NVB-mediated cell death in PARPi-resistant cells arises from increased double-strand break end resection, leading to accumulation of single-strand DNA intermediates and non-functional RAD51 foci. Our results demonstrate that NVB may be useful alone or in combination with PARPi in treating HR-deficient tumors, including those with acquired PARPi resistance. (151/150).

• Publisher: Nature Publishing Group
• Subject: Adenosine Triphosphatases - genetics / Chemotherapy / DNA damage / DNA repair / Enzymes / Experiments / Female / Homologous Recombination - genetics / Humans / Mutation / Ovarian Neoplasms - drug therapy / Ovaries / Poly(ADP-ribose) Polymerase Inhibitors - pharmacology / Proteins / Tumors