Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance.
Nat Commun
; 12(1): 3636, 2021 06 17.
Article
in En
| MEDLINE
| ID: mdl-34140467
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Nucleic Acid Synthesis Inhibitors
/
BRCA1 Protein
/
BRCA2 Protein
/
DNA-Directed DNA Polymerase
/
DNA Repair
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Poly(ADP-ribose) Polymerase Inhibitors
/
Synthetic Lethal Mutations
Limits:
Animals
/
Female
/
Humans
Language:
En
Journal:
Nat Commun
Journal subject:
BIOLOGIA
/
CIENCIA
Year:
2021
Document type:
Article
Affiliation country: