| Title: |
CX-5461 is a DNA G-quadruplex stabilizer with selective lethality in BRCA1/2 deficient tumours. |
| Authors: |
Xu, H; Di Antonio, M; McKinney, S; Mathew, V; Ho, B; O'Neil, NJ; Santos, ND; Silvester, J; Wei, V; Garcia, J; Kabeer, F; Lai, D; Soriano, P; Banáth, J; Chiu, DS; Yap, D; Le, DD; Ye, FB; Zhang, A; Thu, K; Soong, J; Lin, S-C; Tsai, AHC; Osako, T; Algara, T; Saunders, DN; Wong, J; Xian, J; Bally, MB; Brenton, JD; Brown, GW; Shah, SP; Cescon, D; Mak, TW; Caldas, C; Stirling, PC; Hieter, P; Balasubramanian, S; Aparicio, S |
| Publisher Information: |
Nature Publishing Group; //doi.org/10.1038/ncomms14432; Nature Communications |
| Publication Year: |
2017 |
| Collection: |
Apollo - University of Cambridge Repository |
| Subject Terms: |
Animals; BRCA1 Protein; BRCA2 Protein; Base Sequence; Benzothiazoles; Benzoxazines; 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 |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
https://www.repository.cam.ac.uk/handle/1810/263110 |
| DOI: |
10.17863/CAM.8413 |
| Availability: |
https://www.repository.cam.ac.uk/handle/1810/263110; https://doi.org/10.17863/CAM.8413 |
| Rights: |
Attribution 4.0 International ; https://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.95496BF4 |
| Database: |
BASE |