Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance

To recognize methods to target DNA repair vulnerabilities in cancer, we discovered nanomolar potent, selective, low molecular weight (MW), allosteric inhibitors from the polymerase purpose of DNA polymerase Pol?, including ART558. ART558 inhibits the main Pol?-mediated DNA repair process, Theta-Mediated Finish Joining, without targeting Non-Homologous Finish Joining. Additionally, ART558 elicits DNA damage and artificial lethality in BRCA1- or BRCA2-mutant tumor cells and improves the results of a PARP inhibitor. Genetic perturbation screening says defects within the 53BP1/Shieldin complex, which cause PARP inhibitor resistance, lead to in vitro as well as in vivo sensitivity to small molecule Pol? polymerase inhibitors. Mechanistically, ART558 increases biomarkers of single-stranded DNA and artificial lethality in 53BP1-defective cells although the inhibition of DNA nucleases that promote finish-resection reversed these effects, implicating these within the synthetic lethal mechanism-of-action. Taken together, these observations describe a medication class that elicits BRCA-gene synthetic lethality and PARP inhibitor synergy, in addition to targeting a biomarker-defined mechanism of PARPi-resistance.