Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance
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Published:2021-06-17
Issue:1
Volume:12
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Zatreanu Diana, Robinson Helen M. R., Alkhatib Omar, Boursier Marie, Finch Harry, Geo Lerin, Grande DiegoORCID, Grinkevich Vera, Heald Robert A., Langdon Sophie, Majithiya Jayesh, McWhirter ClaireORCID, Martin Niall M. B., Moore Shaun, Neves Joana, Rajendra EesonORCID, Ranzani Marco, Schaedler Theresia, Stockley Martin, Wiggins Kimberley, Brough Rachel, Sridhar Sandhya, Gulati Aditi, Shao Nan, Badder Luned M., Novo Daniela, Knight Eleanor G., Marlow Rebecca, Haider SyedORCID, Callen Elsa, Hewitt Graeme, Schimmel Joost, Prevo Remko, Alli Christina, Ferdinand Amanda, Bell Cameron, Blencowe Peter, Bot ChrisORCID, Calder Mathew, Charles Mark, Curry Jayne, Ekwuru TennysonORCID, Ewings Katherine, Krajewski Wojciech, MacDonald Ellen, McCarron Hollie, Pang Leon, Pedder Chris, Rigoreau Laurent, Swarbrick MartinORCID, Wheatley Ed, Willis Simon, Wong Ai Ching, Nussenzweig Andre, Tijsterman MarcelORCID, Tutt Andrew, Boulton Simon J.ORCID, Higgins Geoff S., Pettitt Stephen J.ORCID, Smith Graeme C. M.ORCID, Lord Christopher J.ORCID
Abstract
AbstractTo 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.
Funder
Breast Cancer Now National Centre for the Replacement Refinement and Reduction of Animals in Research Cancer Research UK
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
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