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

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

doi:10.1038/s43018-021-00203-x

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. Epub 2021 Jun 17.

Authors

Jia Zhou¹, Camille Gelot², Constantia Pantelidou³, Adam Li¹, Hatice Yücel², Rachel E Davis⁴, Anniina Färkkilä¹, Bose Kochupurakkal¹, Aleem Syed⁵, Geoffrey I Shapiro^{3

6}, John A Tainer⁵, Brian S J Blagg⁴, Raphael Ceccaldi⁷, 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].

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).

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adenosine Triphosphatases / genetics
Female
Homologous Recombination* / genetics
Humans
Ovarian Neoplasms* / drug therapy
Poly(ADP-ribose) Polymerase Inhibitors / pharmacology

Substances

Poly(ADP-ribose) Polymerase Inhibitors
Adenosine Triphosphatases

Abstract

Publication types

MeSH terms

Substances

Grants and funding