| First Author | Zhou J | Year | 2021 |
| Journal | Nat Cancer | Volume | 2 |
| Issue | 6 | Pages | 598-610 |
| PubMed ID | 34179826 | Mgi Jnum | J:307136 |
| Mgi Id | MGI:6718682 | Doi | 10.1038/s43018-021-00203-x |
| Citation | Zhou J, et al. (2021) A first-in-class Polymerase Theta Inhibitor selectively targets Homologous-Recombination-Deficient Tumors. Nat Cancer 2(6):598-610 |
| abstractText | DNA polymerase theta (POLtheta) 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 POLtheta inhibitor that selectively kills HR-deficient tumor cells in vitro and in vivo. NVB directly binds to the POLtheta ATPase domain, inhibits its ATPase activity, and phenocopies POLtheta depletion. NVB kills HR-deficient breast and ovarian tumors in GEMM, xenograft and PDX models. Increased POLtheta levels predict NVB sensitivity, and BRCA-deficient tumor cells with acquired resistance to 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-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). |
