Abstract P056: Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance
Authors: Zatreanu Diana A. , Robinson Helen M. R. , Alkhatib Omar , Boursier Marie , Finch Harry , Geo Lerin , Grande Diego , Grinkevich Vera , Heald Robert , Langdon Sophie , Majithiya Jayesh , McWhirter Claire , Martin Niall M. B. , Moore Shaun , Neves Joana , Rajendra Eeson , 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 Syed , Callen Elsa , Hewitt Graeme , Schimmel Joost , Prevo Remko , Alli Christina , Ferdinand Amanda , Bell Cameron , Blencowe Peter , Calder Mathew , Charles Mark , Curry Jayne , Ekwuru Tennyson , Ewings Katherine , Nussenzweig Andre , Tijsterman Marcel , Tutt Andrew , Boulton Simon J. , Higgins Geoff S. , Pettitt Steve , Smith Graeme C. M. , Lord Christopher J. 
Published: December 2021

To target DNA repair vulnerabilities in cancer, we discovered nanomolar potent, selective, low molecular weight, allosteric inhibitors of the polymerase function of DNA polymerase Theta (Polθ), including ART558. ART558 inhibits the major Polθ-mediated DNA repair process, Theta-Mediated End Joining (TMEJ), without targeting Non-Homologous End Joining. Moreover, we show that exposure to ART558 can elicit 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 are a cause of PARP inhibitor resistance, result in in vitro and in vivo sensitivity to Polθ polymerase inhibitors. Mechanistically, ART558 increases biomarkers of single-stranded DNA and synthetic lethality in 53BP1-defective cells. The inhibition of DNA nucleases that promote end-resection reversed these effects, suggesting that resection via Exo1 or Blm-Dna2 being a cause, at least in part, of the ART558 sensitivity phenotype. 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.

Citation Format: Diana A. Zatreanu, Helen M. R. Robinson, Omar Alkhatib, Marie Boursier, Harry Finch, Lerin Geo, Diego Grande, Vera Grinkevich, Robert 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, Mathew Calder, Mark Charles, Jayne Curry, Tennyson Ekwuru, Katherine Ewings, Andre Nussenzweig, Marcel Tijsterman, Andrew Tutt, Simon J. Boulton, Geoff S. Higgins, Steve Pettitt, Graeme C. M. Smith, Christopher J. Lord. Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P056.