CX-5461 is a DNA G-quadruplex stabilizer with selective lethality in BRCA1/2 deficient tumours.
Di, Antonio Marco
Nature Publishing Group
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Xu, H., Di, A. M., McKinney, S., Mathew, V., Ho, B., O'Neil, N., Santos, N., et al. CX-5461 is a DNA G-quadruplex stabilizer with selective lethality in BRCA1/2 deficient tumours.. Nature Communications, 8 (14432)https://doi.org/10.1038/ncomms14432
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).
This work was supported by the 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 Grant MOP-126119, Canada Foundation for Innovation and Cancer Research UK. Grant Brown lab is supported by CCSRI Impact Grant 702310 (to G.W.B.) and Ontario Government Scholarship (to B.H.). S.A. is supported by a Canada Research Chair in Molecular Oncology. The Balasubramanian lab is supported by a programme grant (C14303/A17197) and core funding (C14303/A17197) from Cancer Research UK.
External DOI: https://doi.org/10.1038/ncomms14432
This record's URL: https://www.repository.cam.ac.uk/handle/1810/263110
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