Journal
NATURE COMMUNICATIONS
Volume 8, Issue -, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/ncomms14432
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Funding
- Canadian Breast Cancer Foundation BC/Yukon
- BC Cancer Foundation
- Stand Up to Cancer Canada [SU2C-AACR-DT-18-15]
- TFRI Grant [1021]
- CCSRI Grant [701584]
- CIHR [MOP-126119]
- Canada Foundation for Innovation
- Cancer Research UK
- CCSRI Impact Grant [702310]
- Ontario Government Scholarship
- Canada Research Chair in Molecular Oncology
- Cancer Research UK [C14303/A17197]
- Cancer Research UK [18618, 19836, 15601] Funding Source: researchfish
- Healthway
- Cancer Research UK [22905] Funding Source: researchfish
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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).
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