Anti-tumoral activity of the G-quadruplex ligand pyridostatin against BRCA1/2-deficient tumours

Targeted therapies against BRCA1/2-mutated tumours introduce DNA lesions in tumour cells. Ligands that bind and stabilise G-quadruplexes (G4s) have recently emerged as a class of compounds that selectively eliminate cells and tumours lacking BRCA1/2. Pyridostatin is a small molecule that binds G4s and is specifically toxic to BRCA1/2-deficient cells in vitro. However, its in vivo potential has not yet been evaluated. Here we demonstrate that pyridostatin exhibits a high specific activity against BRCA1/2-deficient tumours, including PARPi resistant patient-derived xenograft tumours. Mechanistically, we demonstrate that pyridostatin disrupts replication leading to DNA double-stranded breaks that can be repaired in the absence of BRCA1/2 by canonical non-homologous end joining (C-NHEJ). Consistent with this, chemical inhibitors of DNA-PKcs, a core component of C-NHEJ kinase activity, act synergistically with pyridostatin in eliminating BRCA1/2-deficient tumours. Furthermore, we demonstrate that pyridostatin triggers cGAS/STING-dependent innate immune responses when BRCA1/2 are abrogated. Overall, our results demonstrate that pyridostatin is a compound suitable for further therapeutic development, alone or in combination with paclitaxel and DNA-PKcs inhibitors, for the benefit of cancer patients carrying BRCA1/2 mutations.