title: CX-5461 is a DNA G-quadruplex stabilizer with selective lethality in BRCA1/2 deficient tumours.
abstract: 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).
authors.affiliation: Department of Molecular Oncology, British Columbia Cancer Research Centre, and Department of Pathology and Laboratory Medicine, University of British Columbia, 675 West 10th Avenue, Vancouver, British Columbia, Canada V5Z 1L3.
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authors.affiliation: Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.|Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
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authors.affiliation: Department of Molecular Oncology, British Columbia Cancer Research Centre, and Department of Pathology and Laboratory Medicine, University of British Columbia, 675 West 10th Avenue, Vancouver, British Columbia, Canada V5Z 1L3.
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authors.identifier: 0000-0002-1611-0867
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authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia, Canada V5Z 1L3.
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authors.affiliation: Department of Molecular Oncology, British Columbia Cancer Research Centre, and Department of Pathology and Laboratory Medicine, University of British Columbia, 675 West 10th Avenue, Vancouver, British Columbia, Canada V5Z 1L3.
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authors.affiliation: Department of Molecular Oncology, British Columbia Cancer Research Centre, and Department of Pathology and Laboratory Medicine, University of British Columbia, 675 West 10th Avenue, Vancouver, British Columbia, Canada V5Z 1L3.
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authors.affiliation: Department of Molecular Oncology, British Columbia Cancer Research Centre, and Department of Pathology and Laboratory Medicine, University of British Columbia, 675 West 10th Avenue, Vancouver, British Columbia, Canada V5Z 1L3.
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authors.affiliation: Department of Molecular Oncology, British Columbia Cancer Research Centre, and Department of Pathology and Laboratory Medicine, University of British Columbia, 675 West 10th Avenue, Vancouver, British Columbia, Canada V5Z 1L3.
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authors.affiliation: Department of Molecular Oncology, British Columbia Cancer Research Centre, and Department of Pathology and Laboratory Medicine, University of British Columbia, 675 West 10th Avenue, Vancouver, British Columbia, Canada V5Z 1L3.
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authors.affiliation: Department of Molecular Oncology, British Columbia Cancer Research Centre, and Department of Pathology and Laboratory Medicine, University of British Columbia, 675 West 10th Avenue, Vancouver, British Columbia, Canada V5Z 1L3.
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authors.affiliation: Department of Molecular Oncology, British Columbia Cancer Research Centre, and Department of Pathology and Laboratory Medicine, University of British Columbia, 675 West 10th Avenue, Vancouver, British Columbia, Canada V5Z 1L3.
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authors.affiliation: Department of Molecular Oncology, British Columbia Cancer Research Centre, and Department of Pathology and Laboratory Medicine, University of British Columbia, 675 West 10th Avenue, Vancouver, British Columbia, Canada V5Z 1L3.
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authors.affiliation: Department of Molecular Oncology, British Columbia Cancer Research Centre, and Department of Pathology and Laboratory Medicine, University of British Columbia, 675 West 10th Avenue, Vancouver, British Columbia, Canada V5Z 1L3.
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authors.affiliation: Department of Molecular Oncology, British Columbia Cancer Research Centre, and Department of Pathology and Laboratory Medicine, University of British Columbia, 675 West 10th Avenue, Vancouver, British Columbia, Canada V5Z 1L3.
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mesh_terms: D000818:Animals; D019313:BRCA1 Protein / Q000172:deficiency*; D024682:BRCA2 Protein / Q000172:deficiency*; D001483:Base Sequence; D052160:Benzothiazoles / Q000494:pharmacology* / Q000627:therapeutic use*; D048588:Benzoxazines / Q000494:pharmacology; D017173:Caenorhabditis elegans / Q000187:drug effects; D045744:Cell Line, Tumor; D043171:Chromosomal Instability / Q000235:genetics; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D004275:DNA, Ribosomal / Q000235:genetics; D005260:Female; D054856:G-Quadruplexes / Q000187:drug effects; D015894:Genome, Human; D005838:Genotype; D059765:Homologous Recombination / Q000187:drug effects; D006801:Humans; D051379:Mice; D009287:Naphthyridines / Q000494:pharmacology* / Q000627:therapeutic use*; D009369:Neoplasms / Q000188:drug therapy*; D015363:Quinolones / Q000494:pharmacology; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein; D052160:Benzothiazoles; D048588:Benzoxazines; C545184:CX 3543; C557717:CX 5461; D004275:DNA, Ribosomal; D009287:Naphthyridines; D015363:Quinolones