A first-in-class Polymerase Theta Inhibitor selectively targets Homologous-Recombination-Deficient Tumors

  • Nat Cancer. 2021 Jun;2(6):598-610. doi: 10.1038/s43018-021-00203-x.
Jia Zhou  1 ,  Camille Gelot  2 ,  Constantia Pantelidou  3 ,  Adam Li  1 ,  Hatice Yücel  2 ,  Rachel E Davis  4 ,  Anniina Färkkilä  1 ,  Bose Kochupurakkal  1 ,  Aleem Syed  5 ,  Geoffrey I Shapiro  3  6 ,  John A Tainer  5 ,  Brian S J Blagg  4 ,  Raphael Ceccaldi  7 ,  Alan D D'Andrea  8  9  10
Affiliations
  • 1. Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
  • 2. Inserm U830, PSL Research University, Institut Curie, Paris, France.
  • 3. Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, MA, USA.
  • 4. Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA.
  • 5. Departments of Cancer Biology and Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 6. Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 7. Inserm U830, PSL Research University, Institut Curie, Paris, France. [email protected].
  • 8. Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. [email protected].
  • 9. Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
  • 10. Susan F. Smith Center for Women's Cancers, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
PMID: 34179826 DOI: 10.1038/s43018-021-00203-x
Abstract

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 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 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 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).

Keywords
Fanconi Anemia; HRD cancer; Homologous Recombination; MMEJ; Novobiocin; PARP inhibitor resistance; Polymerase theta (POLθ).
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