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

Hong Xu, Marco Di Antonio, Steven McKinney, Veena Mathew, Brandon Ho, Nigel J. O’Neil, Nancy Dos Santos, Jennifer Silvester, Vivien Wei, Jessica Garcia, Farhia Kabeer, Daniel Lai, Priscilla Soriano, Judit Banáth, Derek S. Chiu, Damian Yap, Daniel D. Le, Frank B. Ye, Anni Zhang, Kelsie Thu, John Soong, Shu-chuan Lin, Angela Hsin Chin Tsai, Tomo Osako, Teresa Algara, Darren N. Saunders, Jason Wong, Jian Xian, Marcel B. Bally, James D. Brenton, Grant W. Brown, Sohrab P. Shah, David Cescon, Tak W. Mak, Carlos Caldas, Peter C. Stirling, Phil Hieter, Shankar Balasubramanian and Samuel Aparicio ()
Additional contact information
Hong Xu: British Columbia Cancer Research Centre, University of British Columbia
Marco Di Antonio: Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Robinson Way,
Steven McKinney: British Columbia Cancer Research Centre, University of British Columbia
Veena Mathew: Terry Fox Laboratory, BC Cancer Agency
Brandon Ho: University of Toronto
Nigel J. O’Neil: Michael Smith Laboratories, University of British Columbia
Nancy Dos Santos: Advanced Therapeutics, University of British Columbia
Jennifer Silvester: Campbell Family Institute for Breast Cancer Research, Princess Margret Cancer Centre
Vivien Wei: British Columbia Cancer Research Centre, University of British Columbia
Jessica Garcia: British Columbia Cancer Research Centre, University of British Columbia
Farhia Kabeer: British Columbia Cancer Research Centre, University of British Columbia
Daniel Lai: British Columbia Cancer Research Centre, University of British Columbia
Priscilla Soriano: British Columbia Cancer Research Centre, University of British Columbia
Judit Banáth: BC Cancer Agency
Derek S. Chiu: British Columbia Cancer Research Centre, University of British Columbia
Damian Yap: British Columbia Cancer Research Centre, University of British Columbia
Daniel D. Le: Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Robinson Way,
Frank B. Ye: Michael Smith Laboratories, University of British Columbia
Anni Zhang: Terry Fox Laboratory, BC Cancer Agency
Kelsie Thu: Campbell Family Institute for Breast Cancer Research, Princess Margret Cancer Centre
John Soong: Senhwa Biosciences, Inc.
Shu-chuan Lin: Senhwa Biosciences, Inc.
Angela Hsin Chin Tsai: British Columbia Cancer Research Centre, University of British Columbia
Tomo Osako: British Columbia Cancer Research Centre, University of British Columbia
Teresa Algara: British Columbia Cancer Research Centre, University of British Columbia
Darren N. Saunders: British Columbia Cancer Research Centre, University of British Columbia
Jason Wong: British Columbia Cancer Research Centre, University of British Columbia
Jian Xian: University of Cambridge, Li Ka Shing Centre
Marcel B. Bally: Advanced Therapeutics, University of British Columbia
James D. Brenton: University of Cambridge, Li Ka Shing Centre
Grant W. Brown: University of Toronto
Sohrab P. Shah: British Columbia Cancer Research Centre, University of British Columbia
David Cescon: Campbell Family Institute for Breast Cancer Research, Princess Margret Cancer Centre
Tak W. Mak: Campbell Family Institute for Breast Cancer Research, Princess Margret Cancer Centre
Carlos Caldas: University of Cambridge, Li Ka Shing Centre
Peter C. Stirling: Terry Fox Laboratory, BC Cancer Agency
Phil Hieter: Michael Smith Laboratories, University of British Columbia
Shankar Balasubramanian: Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Robinson Way,
Samuel Aparicio: British Columbia Cancer Research Centre, University of British Columbia

Nature Communications, 2017, vol. 8, issue 1, 1-18

Abstract: 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).

Date: 2017
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/ncomms14432 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14432

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/ncomms14432

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().