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CX-5461 is a DNA G-quadruplex stabilizer with selective lethality in BRCA1/2 deficient tumours.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Xu, H 
McKinney, S 
Mathew, V 
Ho, B 

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).

Description

Keywords

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

Journal Title

Nature Communications

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

8

Publisher

Nature Publishing Group
Sponsorship
Cancer Research UK (18618)
Cancer Research UK (22905)
Cancer Research UK (15601)
Cancer Research UK (19836)
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.