2. Academic Validation
  3. A first-in-class Polymerase Theta Inhibitor selectively targets Homologous-Recombination-Deficient Tumors

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

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. raphael.ceccaldi@curie.fr.
  • 8 Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. alan_dandrea@dfci.harvard.edu.
  • 9 Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, MA, USA. alan_dandrea@dfci.harvard.edu.
  • 10 Susan F. Smith Center for Women's Cancers, Dana-Farber Cancer Institute, Boston, MA, USA. alan_dandrea@dfci.harvard.edu.
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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