دورية أكاديمية
Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance.
| العنوان: | Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance. |
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| المؤلفون: | Zatreanu, D, Robinson, HMR, Alkhatib, O, Boursier, M, Finch, H, Geo, L, Grande, D, Grinkevich, V, Heald, RA, Langdon, S, Majithiya, J, McWhirter, C, Martin, NMB, Moore, S, Neves, J, Rajendra, E, Ranzani, M, Schaedler, T, Stockley, M, Wiggins, K, Brough, R, Sridhar, S, Gulati, A, Shao, N, Badder, LM, Novo, D, Knight, EG, Marlow, R, Haider, S, Callen, E, Hewitt, G, Schimmel, J, Prevo, R, Alli, C, Ferdinand, A, Bell, C, Blencowe, P, Bot, C, Calder, M, Charles, M, Curry, J, Ekwuru, T, Ewings, K, Krajewski, W, MacDonald, E, McCarron, H, Pang, L, Pedder, C, Rigoreau, L, Swarbrick, M, Wheatley, E, Willis, S, Wong, AC, Nussenzweig, A, Tijsterman, M, Tutt, A, Boulton, SJ, Higgins, GS, Pettitt, SJ, Smith, GCM, Lord, CJ |
| المساهمون: | Haider, Syed, Pettitt, Stephen, Lord, Christopher |
| سنة النشر: | 2021 |
| المجموعة: | The Institute of Cancer Research (ICR): Publications Repository |
| مصطلحات موضوعية: | Organoids, Cell Line, Tumor, Animals, Humans, Mice, Rats, Ovarian Neoplasms, DNA Damage, Deoxyribonucleases, DNA-Directed DNA Polymerase, Cell Cycle Proteins, DNA-Binding Proteins, BRCA1 Protein, BRCA2 Protein, Nucleic Acid Synthesis Inhibitors, Drug Screening Assays, Antitumor, Inhibitory Concentration 50, Apoptosis, Cell Proliferation, Cell Survival, DNA Repair, Allosteric Regulation, Drug Resistance, Neoplasm, Female, Homologous Recombination, Poly(ADP-ribose) Polymerase Inhibitors, Tumor Suppressor p53-Binding Protein 1 |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | Electronic; ?; application/pdf |
| اللغة: | English |
| تدمد: | 2041-1723 |
| العلاقة: | Nature communications, 2021, 12 (1), pp. 3636 - ?; https://repository.icr.ac.uk/handle/internal/4762Test |
| DOI: | 10.1038/s41467-021-23463-8 |
| الإتاحة: | https://doi.org/10.1038/s41467-021-23463-8Test https://repository.icr.ac.uk/handle/internal/4762Test |
| حقوق: | https://creativecommons.org/licenses/by/4.0Test |
| رقم الانضمام: | edsbas.3E817975 |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 20411723 |
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| DOI: | 10.1038/s41467-021-23463-8 |