Nature Communications (Jun 2021)
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,
- Christopher J. Lord
Affiliations
- Diana Zatreanu
- CRUK Gene Function Laboratory, The Institute of Cancer Research
- Helen M. R. Robinson
- Artios Pharma, The Glenn Berge Building, Babraham Research Campus
- Omar Alkhatib
- Artios Pharma, The Glenn Berge Building, Babraham Research Campus
- Marie Boursier
- Artios Pharma, The Glenn Berge Building, Babraham Research Campus
- Harry Finch
- Artios Pharma, The Glenn Berge Building, Babraham Research Campus
- Lerin Geo
- Artios Pharma, The Glenn Berge Building, Babraham Research Campus
- Diego Grande
- Artios Pharma, The Glenn Berge Building, Babraham Research Campus
- Vera Grinkevich
- Artios Pharma, The Glenn Berge Building, Babraham Research Campus
- Robert A. Heald
- Artios Pharma, The Glenn Berge Building, Babraham Research Campus
- Sophie Langdon
- Artios Pharma, The Glenn Berge Building, Babraham Research Campus
- Jayesh Majithiya
- Artios Pharma, The Glenn Berge Building, Babraham Research Campus
- Claire McWhirter
- Artios Pharma, The Glenn Berge Building, Babraham Research Campus
- Niall M. B. Martin
- Artios Pharma, The Glenn Berge Building, Babraham Research Campus
- Shaun Moore
- Artios Pharma, The Glenn Berge Building, Babraham Research Campus
- Joana Neves
- Artios Pharma, The Glenn Berge Building, Babraham Research Campus
- Eeson Rajendra
- Artios Pharma, The Glenn Berge Building, Babraham Research Campus
- Marco Ranzani
- Artios Pharma, The Glenn Berge Building, Babraham Research Campus
- Theresia Schaedler
- Artios Pharma, The Glenn Berge Building, Babraham Research Campus
- Martin Stockley
- Artios Pharma, The Glenn Berge Building, Babraham Research Campus
- Kimberley Wiggins
- Artios Pharma, The Glenn Berge Building, Babraham Research Campus
- Rachel Brough
- CRUK Gene Function Laboratory, The Institute of Cancer Research
- Sandhya Sridhar
- CRUK Gene Function Laboratory, The Institute of Cancer Research
- Aditi Gulati
- CRUK Gene Function Laboratory, The Institute of Cancer Research
- Nan Shao
- CRUK Gene Function Laboratory, The Institute of Cancer Research
- Luned M. Badder
- The Breast Cancer Now Research Unit, King’s College London
- Daniela Novo
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research
- Eleanor G. Knight
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research
- Rebecca Marlow
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research
- Syed Haider
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research
- Elsa Callen
- Laboratory of Genome Integrity, National Cancer Institute, NIH
- Graeme Hewitt
- The Francis Crick Institute
- Joost Schimmel
- Department of Human Genetics, Leiden University Medical Center
- Remko Prevo
- Medical Research Council Oxford Institute for Radiation Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive
- Christina Alli
- Cancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus
- Amanda Ferdinand
- Cancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus
- Cameron Bell
- Cancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus
- Peter Blencowe
- Cancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus
- Chris Bot
- Cancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus
- Mathew Calder
- Cancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus
- Mark Charles
- Cancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus
- Jayne Curry
- Cancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus
- Tennyson Ekwuru
- Cancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus
- Katherine Ewings
- Cancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus
- Wojciech Krajewski
- Cancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus
- Ellen MacDonald
- Cancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus
- Hollie McCarron
- Cancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus
- Leon Pang
- Cancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus
- Chris Pedder
- Cancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus
- Laurent Rigoreau
- Cancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus
- Martin Swarbrick
- Cancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus
- Ed Wheatley
- Cancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus
- Simon Willis
- Cancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus
- Ai Ching Wong
- Cancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus
- Andre Nussenzweig
- Laboratory of Genome Integrity, National Cancer Institute, NIH
- Marcel Tijsterman
- Department of Human Genetics, Leiden University Medical Center
- Andrew Tutt
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research
- Simon J. Boulton
- Artios Pharma, The Glenn Berge Building, Babraham Research Campus
- Geoff S. Higgins
- Medical Research Council Oxford Institute for Radiation Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive
- Stephen J. Pettitt
- CRUK Gene Function Laboratory, The Institute of Cancer Research
- Graeme C. M. Smith
- Artios Pharma, The Glenn Berge Building, Babraham Research Campus
- Christopher J. Lord
- CRUK Gene Function Laboratory, The Institute of Cancer Research
- DOI
- https://doi.org/10.1038/s41467-021-23463-8
- Journal volume & issue
-
Vol. 12,
no. 1
pp. 1 – 15
Abstract
Polθ has been recently identified as a therapeutic target in cancer but specific inhibitors are currently unavailable. Here, the authors identify small molecule inhibitors of Polθ’s polymerase activity which elicit BRCA1/2 synthetic lethality, enhance the effect of PARP inhibitors and target PARP inhibitor resistance caused by 53BP1/Shieldin pathway defects.
