Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance

Diana Zatreanu, Helen M. R. Robinson, Omar Alkhatib, Marie Boursier, Harry Finch, Lerin Geo, Diego Grande, Vera Grinkevich, Robert A. Heald, Sophie Langdon, Jayesh Majithiya, Claire McWhirter, Niall M. B. Martin, Shaun Moore, Joana Neves, Eeson Rajendra, Marco Ranzani, Theresia Schaedler, Martin Stockley, Kimberley Wiggins, Rachel Brough, Sandhya Sridhar, Aditi Gulati, Nan Shao, Luned M. Badder, Daniela Novo, Eleanor G. Knight, Rebecca Marlow, Syed Haider, Elsa Callen, Graeme Hewitt, Joost Schimmel, Remko Prevo, Christina Alli, Amanda Ferdinand, Cameron Bell, Peter Blencowe, Chris Bot, Mathew Calder, Mark Charles, Jayne Curry, Tennyson Ekwuru, Katherine Ewings, Wojciech Krajewski, Ellen MacDonald, Hollie McCarron, Leon Pang, Chris Pedder, Laurent Rigoreau, Martin Swarbrick, Ed Wheatley, Simon Willis, Ai Ching Wong, Andre Nussenzweig, Marcel Tijsterman, Andrew Tutt, Simon J. Boulton, Geoff S. Higgins, Stephen J. Pettitt (), Graeme C. M. Smith () and Christopher J. Lord ()
Additional contact information
Diana Zatreanu: The Institute of Cancer Research
Helen M. R. Robinson: The Glenn Berge Building, Babraham Research Campus
Omar Alkhatib: The Glenn Berge Building, Babraham Research Campus
Marie Boursier: The Glenn Berge Building, Babraham Research Campus
Harry Finch: The Glenn Berge Building, Babraham Research Campus
Lerin Geo: The Glenn Berge Building, Babraham Research Campus
Diego Grande: The Glenn Berge Building, Babraham Research Campus
Vera Grinkevich: The Glenn Berge Building, Babraham Research Campus
Robert A. Heald: The Glenn Berge Building, Babraham Research Campus
Sophie Langdon: The Glenn Berge Building, Babraham Research Campus
Jayesh Majithiya: The Glenn Berge Building, Babraham Research Campus
Claire McWhirter: The Glenn Berge Building, Babraham Research Campus
Niall M. B. Martin: The Glenn Berge Building, Babraham Research Campus
Shaun Moore: The Glenn Berge Building, Babraham Research Campus
Joana Neves: The Glenn Berge Building, Babraham Research Campus
Eeson Rajendra: The Glenn Berge Building, Babraham Research Campus
Marco Ranzani: The Glenn Berge Building, Babraham Research Campus
Theresia Schaedler: The Glenn Berge Building, Babraham Research Campus
Martin Stockley: The Glenn Berge Building, Babraham Research Campus
Kimberley Wiggins: The Glenn Berge Building, Babraham Research Campus
Rachel Brough: The Institute of Cancer Research
Sandhya Sridhar: The Institute of Cancer Research
Aditi Gulati: The Institute of Cancer Research
Nan Shao: The Institute of Cancer Research
Luned M. Badder: The Breast Cancer Now Research Unit, King’s College London
Daniela Novo: The Institute of Cancer Research
Eleanor G. Knight: The Institute of Cancer Research
Rebecca Marlow: The Institute of Cancer Research
Syed Haider: The Institute of Cancer Research
Elsa Callen: National Cancer Institute, NIH
Graeme Hewitt: The Francis Crick Institute
Joost Schimmel: Leiden University Medical Center
Remko Prevo: University of Oxford, Old Road Campus Research Building, Roosevelt Drive
Christina Alli: Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus
Amanda Ferdinand: Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus
Cameron Bell: Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus
Peter Blencowe: Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus
Chris Bot: Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus
Mathew Calder: Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus
Mark Charles: Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus
Jayne Curry: Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus
Tennyson Ekwuru: Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus
Katherine Ewings: Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus
Wojciech Krajewski: Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus
Ellen MacDonald: Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus
Hollie McCarron: Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus
Leon Pang: Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus
Chris Pedder: Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus
Laurent Rigoreau: Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus
Martin Swarbrick: Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus
Ed Wheatley: Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus
Simon Willis: Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus
Ai Ching Wong: Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus
Andre Nussenzweig: National Cancer Institute, NIH
Marcel Tijsterman: Leiden University Medical Center
Andrew Tutt: The Institute of Cancer Research
Simon J. Boulton: The Glenn Berge Building, Babraham Research Campus
Geoff S. Higgins: University of Oxford, Old Road Campus Research Building, Roosevelt Drive
Stephen J. Pettitt: The Institute of Cancer Research
Graeme C. M. Smith: The Glenn Berge Building, Babraham Research Campus
Christopher J. Lord: The Institute of Cancer Research

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract To identify approaches to target DNA repair vulnerabilities in cancer, we discovered nanomolar potent, selective, low molecular weight (MW), allosteric inhibitors of the polymerase function of DNA polymerase Polθ, including ART558. ART558 inhibits the major Polθ-mediated DNA repair process, Theta-Mediated End Joining, without targeting Non-Homologous End Joining. In addition, ART558 elicits DNA damage and synthetic lethality in BRCA1- or BRCA2-mutant tumour cells and enhances the effects of a PARP inhibitor. Genetic perturbation screening revealed that defects in the 53BP1/Shieldin complex, which cause PARP inhibitor resistance, result in in vitro and in vivo sensitivity to small molecule Polθ polymerase inhibitors. Mechanistically, ART558 increases biomarkers of single-stranded DNA and synthetic lethality in 53BP1-defective cells whilst the inhibition of DNA nucleases that promote end-resection reversed these effects, implicating these in the synthetic lethal mechanism-of-action. Taken together, these observations describe a drug class that elicits BRCA-gene synthetic lethality and PARP inhibitor synergy, as well as targeting a biomarker-defined mechanism of PARPi-resistance.

Date: 2021
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DOI: 10.1038/s41467-021-23463-8

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