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

Author

Listed:
  • 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,
    University of Cambridge)

  • 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
    University of Toronto)

  • 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,
    University of Cambridge)

  • Samuel Aparicio

    (British Columbia Cancer Research Centre, University of British Columbia)

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).

Suggested Citation

  • 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 & Priscill, 2017. "CX-5461 is a DNA G-quadruplex stabilizer with selective lethality in BRCA1/2 deficient tumours," Nature Communications, Nature, vol. 8(1), pages 1-18, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14432
    DOI: 10.1038/ncomms14432
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    Cited by:

    1. Melvin Pan & Christiane Zorbas & Maki Sugaya & Kensuke Ishiguro & Miki Kato & Miyuki Nishida & Hai-Feng Zhang & Marco M. Candeias & Akimitsu Okamoto & Takamasa Ishikawa & Tomoyoshi Soga & Hiroyuki Abu, 2022. "Glutamine deficiency in solid tumor cells confers resistance to ribosomal RNA synthesis inhibitors," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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