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

Autor: Zatreanu D; CRUK Gene Function Laboratory, The Institute of Cancer Research, London, UK.; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK., Robinson HMR; Artios Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, UK., Alkhatib O; Artios Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, UK., Boursier M; Artios Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, UK., Finch H; Artios Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, UK., Geo L; Artios Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, UK., Grande D; Artios Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, UK., Grinkevich V; Artios Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, UK., Heald RA; Artios Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, UK., Langdon S; Artios Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, UK., Majithiya J; Artios Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, UK., McWhirter C; Artios Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, UK., Martin NMB; Artios Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, UK., Moore S; Artios Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, UK., Neves J; Artios Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, UK., Rajendra E; Artios Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, UK., Ranzani M; Artios Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, UK., Schaedler T; Artios Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, UK., Stockley M; Artios Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, UK., Wiggins K; Artios Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, UK., Brough R; CRUK Gene Function Laboratory, The Institute of Cancer Research, London, UK.; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK., Sridhar S; CRUK Gene Function Laboratory, The Institute of Cancer Research, London, UK.; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK., Gulati A; CRUK Gene Function Laboratory, The Institute of Cancer Research, London, UK.; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK., Shao N; CRUK Gene Function Laboratory, The Institute of Cancer Research, London, UK.; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK., Badder LM; The Breast Cancer Now Research Unit, King's College London, London, UK., Novo D; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK., Knight EG; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK., Marlow R; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.; The Breast Cancer Now Research Unit, King's College London, London, UK., Haider S; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK., Callen E; Laboratory of Genome Integrity, National Cancer Institute, NIH, Bethesda, MD, USA., Hewitt G; The Francis Crick Institute, London, UK., Schimmel J; Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands., Prevo R; Medical Research Council Oxford Institute for Radiation Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, UK., Alli C; Cancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, UK., Ferdinand A; Cancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, UK., Bell C; Cancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, UK., Blencowe P; Cancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, UK., Bot C; Cancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, UK., Calder M; Cancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, UK., Charles M; Cancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, UK., Curry J; Cancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, UK., Ekwuru T; Cancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, UK., Ewings K; Cancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, UK., Krajewski W; Cancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, UK., MacDonald E; Cancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, UK., McCarron H; Cancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, UK., Pang L; Cancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, UK., Pedder C; Cancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, UK., Rigoreau L; Cancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, UK., Swarbrick M; Cancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, UK., Wheatley E; Cancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, UK., Willis S; Cancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, UK., Wong AC; Cancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, UK., Nussenzweig A; Laboratory of Genome Integrity, National Cancer Institute, NIH, Bethesda, MD, USA., Tijsterman M; Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands., Tutt A; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.; The Breast Cancer Now Research Unit, King's College London, London, UK., Boulton SJ; Artios Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, UK.; The Francis Crick Institute, London, UK., Higgins GS; Medical Research Council Oxford Institute for Radiation Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, UK., Pettitt SJ; CRUK Gene Function Laboratory, The Institute of Cancer Research, London, UK. Stephen.Pettitt@icr.ac.uk.; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK. Stephen.Pettitt@icr.ac.uk., Smith GCM; Artios Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, UK. Graeme.Smith@artiospharma.com., Lord CJ; CRUK Gene Function Laboratory, The Institute of Cancer Research, London, UK. Chris.Lord@icr.ac.uk.; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK. Chris.Lord@icr.ac.uk.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2021 Jun 17; Vol. 12 (1), pp. 3636. Date of Electronic Publication: 2021 Jun 17.
DOI: 10.1038/s41467-021-23463-8
Abstrakt: 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.
Databáze: MEDLINE
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