Journal article
Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance
- 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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Supplementary materials, 6.3MB, Terms of use)
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(Preview, Version of record, 31.4MB, Terms of use)
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- Publisher copy:
- 10.1038/s41467-021-23463-8
Authors
- Publisher:
- Springer Nature
- Journal:
- Nature Communications More from this journal
- Volume:
- 12
- Issue:
- 1
- Article number:
- 3636
- Publication date:
- 2021-06-17
- Acceptance date:
- 2021-04-30
- DOI:
- ISSN:
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2041-1723
- Language:
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English
- Keywords:
- Pubs id:
-
1178302
- Local pid:
-
pubs:1178302
- Deposit date:
-
2021-05-24
Terms of use
- Copyright holder:
- Zatreanu et al.
- Copyright date:
- 2021
- Rights statement:
- © The Authors 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
- Licence:
- CC Attribution (CC BY)
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