The DOI matches its Crossref record; 65 of the 65 references it cites were found in a registry or an index.
Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance
Open accessAbstract
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.
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Cites
Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy
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Self-citationSpecific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase
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PARP inhibitors: Synthetic lethality in the clinic
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53BP1 Inhibits Homologous Recombination in Brca1-Deficient Cells by Blocking Resection of DNA Breaks
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Self-citationPrioritization of cancer therapeutic targets using CRISPR–Cas9 screens
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Sgs1 Helicase and Two Nucleases Dna2 and Exo1 Resect DNA Double-Strand Break Ends
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Resistance to therapy caused by intragenic deletion in BRCA2
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Self-citationSae2, Exo1 and Sgs1 collaborate in DNA double-strand break processing
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Cited by
Targeting DNA damage response pathways in cancer
Groelly, F. J., Fawkes, M., Dagg, R. A., Blackford, A. N., & Tarsounas, M. (2023) · Nature Reviews Cancer · doi:10.1038/s41568-022-00535-5 · Cited by 836
Fleury, H., MacEachern, M. K., Stiefel, C. M., Anand, R., Sempeck, C., Nebenfuehr, B., Maurer-Alcalá, K., Ball, K., Proctor, B., Belan, O., et al. (2023) · Molecular Cell · doi:10.1016/j.molcel.2023.03.017 · Cited by 52
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Metadata
- Authors
- Zatreanu, D., Robinson, H. M. R., Alkhatib, O., Boursier, M., Finch, H., Geo, L., Grande, D., Grinkevich, V., Heald, R. A., Langdon, S., Majithiya, J., McWhirter, C., Martin, N. M. B., Moore, S., Neves, J., Rajendra, E., Ranzani, M., Schaedler, T., Stockley, M., Wiggins, K., Brough, R., Sridhar, S., Gulati, A., Shao, N., Badder, L. M., Novo, D., Knight, E. G., 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, A. C., Nussenzweig, A., Tijsterman, M., Tutt, A., Boulton, S. J., Higgins, G. S., Pettitt, S. J., Smith, G. C. M., & Lord, C. J.
- Venue
- Nature Communications
- Published
- 2021-06-17
- Volume
- 12
- Issue
- 1
- Pages
- 3636-3636
- ISSN
- 2041-1723 (ISSN-L)
- OpenAlex
- W3166989335
- Cited by
- 357
- References
- 65
- FWCI
- 17.53
- Type
- journal article
- Language
- en
- Open access
- gold
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- Zatreanu, D., Robinson, H. M. R., Alkhatib, O., Boursier, M., Finch, H., Geo, L., Grande, D., Grinkevich, V., Heald, R. A., Langdon, S., Majithiya, J., McWhirter, C., Martin, N. M. B., Moore, S., Neves, J., Rajendra, E., Ranzani, M., Schaedler, T., Stockley, M., . . . Lord, C. J. (2021). Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance. Nature Communications. https://doi.org/10.1038/s41467-021-23463-8
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