ArticleNature communications2021
Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance.
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Article in Nature communications, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 246 papers.
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246citing papers in PubMed
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Who cites it
246 citing papers in PubMed.
- A Phase II Trial of Niraparib in Patients with Advanced Pancreatic Cancer Harboring Pathogenic Variants in ATM, BRCA1, BRCA2, PALB2, and CHEK2.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Trial
- The CHK1 inhibitor prexasertib in BRCA wild-type platinum-resistant recurrent high-grade serous ovarian carcinoma: a phase 2 trial.Nature communications · 2024Trial
- DNA polymerase theta (Polθ): a novel candidate for targeted cancer therapy.Cancer biology & therapy · 2026Review
- Antitumor activity and structure-activity relationship of poly (ADP-ribose) polymerase (PARP)-based dual inhibitors.Journal of enzyme inhibition and medicinal chemistry · 2026Review
- Expanding the therapeutic scope of PARP inhibitors in breast cancer: current indications and future directions.The Journal of clinical investigation · 2026Review
- The Pharmacologic Profile of ART6043, a First-in-Class Clinical DNA Polymerase Theta Polymerase Domain Inhibitor Potentiating PARP Inhibitor Efficacy.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Article
- Synthetic lethality in cancer: mechanisms, therapeutic exploitation and clinical translation.Signal transduction and targeted therapy · 2026Review
- Targeting Polθ Helicase with RP-3467: Preclinical Validation and Clinical Response in a gmedRxiv : the preprint server for health sciences · 2026Article
- PUM3 is an essential suppressor of replication stress in homologous recombination deficient breast cancer.Nature communications · 2026Article
- Activation of Pol theta-mediated end joining begins during mitotic commitment.bioRxiv : the preprint server for biology · 2026Article
- Exploiting DNA damage tolerance for precision oncology.Trends in cancer · 2026Review
- Precise genomic integration of large DNA fragments by donor-directed annealing using prime editing.Nature biotechnology · 2026Article
- The anion channel GPR89 is a tumor-specific dependency in breast cancer.Nature communications · 2026Article
- PCNA-RECQL5-RPRD1B recruit repair components to stressed replication forks to promote survival of BRCA1-deficient cancer cells.Nucleic acids research · 2026Article
- Disruption of microhomology-mediated end joining in Ewing sarcoma.Molecular cell · 2026Article
- Defective microhomology-mediated end joining inScience advances · 2026Article
- Sam68 stimulates polymerase theta-mediated end-joining by suppressing poison exon inclusion in Polq mRNA.Nucleic acids research · 2026Article
- ZUP1 promotes DNA repair and immune evasion to drive olaparib resistance in triple-negative breast cancer.Journal of advanced research · 2026Article
- Divergent Roles of Canonical and Non-Canonical Mismatch Repair in Regulating Temozolomide Sensitivity in Glioblastoma.International journal of molecular sciences · 2026Review
- Assessing the Clinical Relevance ofCurrent oncology (Toronto, Ont.) · 2026Article
186 more citing papers are in PubMed but not listed here.
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Authors and funding
61 authors.
Diana Zatreanu *CRUK Gene Function Laboratory, The Institute of Cancer Research, London, UK.
Helen M R Robinson *Artios Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, UK.
Omar AlkhatibArtios Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, UK.
Marie BoursierArtios Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, UK.
Harry FinchArtios Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, UK.
Lerin GeoArtios Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, UK.
Diego GrandeArtios Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, UK.ORCID http://orcid.org/0000-0001-6770-9274
Vera GrinkevichArtios Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, UK.
Robert A HealdArtios Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, UK.
Sophie LangdonArtios Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, UK.
Jayesh MajithiyaArtios Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, UK.
Claire McWhirterArtios Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, UK.ORCID http://orcid.org/0000-0003-3316-205X
Niall M B MartinArtios Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, UK.
Shaun MooreArtios Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, UK.
Joana NevesArtios Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, UK.
Eeson RajendraArtios Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, UK.ORCID http://orcid.org/0000-0002-5301-054X
Marco RanzaniArtios Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, UK.
Theresia SchaedlerArtios Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, UK.
Martin StockleyArtios Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, UK.
Kimberley WigginsArtios Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, UK.
Rachel BroughCRUK Gene Function Laboratory, The Institute of Cancer Research, London, UK.
Sandhya SridharCRUK Gene Function Laboratory, The Institute of Cancer Research, London, UK.
Aditi GulatiCRUK Gene Function Laboratory, The Institute of Cancer Research, London, UK.
Nan ShaoCRUK Gene Function Laboratory, The Institute of Cancer Research, London, UK.
Luned M BadderThe Breast Cancer Now Research Unit, King's College London, London, UK.
Daniela NovoThe Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.
Eleanor G KnightThe Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.
Rebecca MarlowThe Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.
Syed HaiderThe Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.ORCID http://orcid.org/0000-0001-6685-5480
Elsa CallenLaboratory of Genome Integrity, National Cancer Institute, NIH, Bethesda, MD, USA.
Graeme HewittThe Francis Crick Institute, London, UK.
Joost SchimmelDepartment of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Remko PrevoMedical Research Council Oxford Institute for Radiation Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, UK.
Christina AlliCancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, UK.
Amanda FerdinandCancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, UK.
Cameron BellCancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, UK.
Peter BlencoweCancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, UK.
Chris BotCancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, UK.ORCID http://orcid.org/0000-0001-6225-4047
Mathew CalderCancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, UK.
Mark CharlesCancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, UK.
Jayne CurryCancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, UK.
Tennyson EkwuruCancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, UK.ORCID http://orcid.org/0000-0003-0070-3403
Katherine EwingsCancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, UK.
Wojciech KrajewskiCancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, UK.
Ellen MacDonaldCancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, UK.
Hollie McCarronCancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, UK.
Leon PangCancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, UK.
Chris PedderCancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, UK.
Laurent RigoreauCancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, UK.
Martin SwarbrickCancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, UK.ORCID http://orcid.org/0000-0001-6942-6067
Ed WheatleyCancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, UK.
Simon WillisCancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, UK.
Ai Ching WongCancer Research UK, Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, UK.
Andre NussenzweigLaboratory of Genome Integrity, National Cancer Institute, NIH, Bethesda, MD, USA.
Marcel TijstermanDepartment of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.ORCID http://orcid.org/0000-0001-8465-9002
Andrew TuttThe Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.
Simon J BoultonArtios Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, UK.ORCID http://orcid.org/0000-0001-6936-6834
Geoff S HigginsMedical Research Council Oxford Institute for Radiation Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, UK.
Stephen J PettittCRUK Gene Function Laboratory, The Institute of Cancer Research, London, UK. Stephen.Pettitt@icr.ac.uk.ORCID http://orcid.org/0000-0003-3313-3857
Graeme C M SmithArtios Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, UK. Graeme.Smith@artiospharma.com.ORCID http://orcid.org/0000-0001-8320-4057
Christopher J LordCRUK Gene Function Laboratory, The Institute of Cancer Research, London, UK. Chris.Lord@icr.ac.uk.ORCID http://orcid.org/0000-0002-3226-0515
Funding
DNA RepairZIABC010283 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI NUSSENZWEIG, ANDRE A. · 2009 to 2025
$27.0MRelationship between DNA damage detection and signalingZIABC010959 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI NUSSENZWEIG, ANDRE A. · 2009 to 2025
$27.0MInvestigating DNA repair vulnerabilities in oncometabolite producing cancersF31CA260794 · NCI · YALE UNIVERSITY · PI NORONHA, KATELYN · 2021 to 2023
$122kCancer Research UK 24439Cancer Research UK 28736Cancer Research UK 28990Cancer Research UK C30061/A24439Department of HealthNCI NIH HHS F31 CA260794
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.
Indexed as
Allosteric RegulationAnimalsApoptosisBRCA1 ProteinBRCA2 ProteinCell Cycle ProteinsCell Line, TumorCell ProliferationCell SurvivalDeoxyribonucleasesDNA-Binding ProteinsDNA DamageDNA-Directed DNA PolymeraseDNA Polymerase thetaDNA RepairDrug Resistance, NeoplasmBRCA1 ProteinBRCA1 protein, humanBRCA2 ProteinBRCA2 protein, humanCell Cycle ProteinsDeoxyribonucleasesDNA-Binding ProteinsDNA-Directed DNA PolymeraseDNA Polymerase thetaNucleic Acid Synthesis InhibitorsPoly(ADP-ribose) Polymerase InhibitorsSHLD1 protein, humanTP53BP1 protein, humanTumor Suppressor p53-Binding Protein 1
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