Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance.
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Date
2021-06-17Author
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
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
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
Synthetic Lethal Mutations
Research team
Gene Function
Gene Function
Language
eng
Date accepted
2021-04-30
License start date
2021-06-17
Citation
Nature communications, 2021, 12 (1), pp. 3636 - ?
Publisher
NATURE RESEARCH
Except where otherwise noted, this item's license is described
as
https://creativecommons.org/licenses/by/4.0
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