cx-5461 and Chromosomal-Instability

G-quadruplex DNAs form four-stranded helical structures and are proposed to play key roles in different cellular processes. Targeting G-quadruplex DNAs for cancer treatment is a very promising prospect. Here, we show that CX-5461 is a G-quadruplex stabilizer, with specific toxicity against BRCA deficiencies in cancer cells and polyclonal patient-derived xenograft models, including tumours resistant to PARP inhibition. Exposure to CX-5461, and its related drug CX-3543, blocks replication forks and induces ssDNA gaps or breaks. The BRCA and NHEJ pathways are required for the repair of CX-5461 and CX-3543-induced DNA damage and failure to do so leads to lethality. These data strengthen the concept of G4 targeting as a therapeutic approach, specifically for targeting HR and NHEJ deficient cancers and other tumours deficient for DNA damage repair. CX-5461 is now in advanced phase I clinical trial for patients with BRCA1/2 deficient tumours (Canadian trial, NCT02719977, opened May 2016).

Topics: Animals; Base Sequence; Benzothiazoles; Benzoxazines; BRCA1 Protein; BRCA2 Protein; Caenorhabditis elegans; Cell Line, Tumor; Chromosomal Instability; DNA Damage; DNA Repair; DNA Replication; DNA, Ribosomal; Female; G-Quadruplexes; Genome, Human; Genotype; Homologous Recombination; Humans; Mice; Naphthyridines; Neoplasms; Quinolones; Saccharomyces cerevisiae; Transcription, Genetic; Xenograft Model Antitumor Assays