| Literature DB >> 34140467 |
Diana Zatreanu1,2, Helen M R Robinson3, Omar Alkhatib3, Marie Boursier3, Harry Finch3, Lerin Geo3, Diego Grande3, Vera Grinkevich3, Robert A Heald3, Sophie Langdon3, Jayesh Majithiya3, Claire McWhirter3, Niall M B Martin3, Shaun Moore3, Joana Neves3, Eeson Rajendra3, Marco Ranzani3, Theresia Schaedler3, Martin Stockley3, Kimberley Wiggins3, Rachel Brough1,2, Sandhya Sridhar1,2, Aditi Gulati1,2, Nan Shao1,2, Luned M Badder4, Daniela Novo2, Eleanor G Knight2, Rebecca Marlow2,4, Syed Haider2, Elsa Callen5, Graeme Hewitt6, Joost Schimmel7, Remko Prevo8, Christina Alli9, Amanda Ferdinand9, Cameron Bell9, Peter Blencowe9, Chris Bot9, Mathew Calder9, Mark Charles9, Jayne Curry9, Tennyson Ekwuru9, Katherine Ewings9, Wojciech Krajewski9, Ellen MacDonald9, Hollie McCarron9, Leon Pang9, Chris Pedder9, Laurent Rigoreau9, Martin Swarbrick9, Ed Wheatley9, Simon Willis9, Ai Ching Wong9, Andre Nussenzweig5, Marcel Tijsterman7, Andrew Tutt2,4, Simon J Boulton3,6, Geoff S Higgins8, Stephen J Pettitt10,11, Graeme C M Smith12, Christopher J Lord13,14.
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.Entities:
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Year: 2021 PMID： 34140467 PMCID： PMC8211653 DOI： 10.1038/s41467-021-23463-8
Source DB: PubMed Journal: Nat Commun ISSN： 2041-1723 Impact factor: 17.694