DNA topoisomerase IIß inhibition blocks DNA end resection and synergizes with PARPi in BRCA1-deficient models

Abstract

DNA end resection is a critical step that governs how a broken chromosome will be repaired. As such, it is heavily regulated by multiple cellular signals and processes. Alterations in the regulation of DNA end resection have consequences for cell survival upon exposure to cytotoxic agents, including those used during cancer chemotherapy. Here, we identified several small molecules that affect the process of DNA end resection. Among them, we focus on determining the mode of action of merbarone, a DNA topoisomerase II inhibitor. We uncover a role of the topoisomerase IIβ isoform in the full processing of DNA breaks. Moreover, we show that the effect of merbarone is affected by the formation of G4 quadruplexes and that BRCA1-deficient cancer cells are sensitive to merbarone. Strikingly, this sensitivity can be partially suppressed in cell lines expressing hypomorphic versions of BRCA1 lacking exon 11, a hypomorph that has been linked to PARPi-resistance. Using cellular models, we show that PARPi- and merbarone-resistant BRCA1 exon 11 mutant cells, but not wildtype BRCA1 cells, are sensitive to the combination of both drugs. Finally, we show that combination of merbarone and the PARPi olaparib has a mild antitumor effect in a PARPi-resistant PDX model bearing a BRCA1 exon 11 mutation.