Open Access

Nature Communications, volume 8, issue 1, publication number 14432

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

Hong Xu ¹

Marco Di Antonio ^{2, 3}

Steven McKinney ¹

Veena Mathew ⁴

Brandon Ho ⁵

Nigel J Oneil ⁶

Nancy Dos Santos ⁷

Jennifer Silvester ⁸

Vivien Wei ¹

Jessica Garcia ¹

Farhia Kabeer ¹

Daniel Lai ¹

Priscilla Soriano ¹

Judit Banáth ⁹

Derek S. Chiu ¹

Damian B.S. Yap ¹

Daniel D Le ²

Frank B Ye ⁶

Anni Zhang ⁴

Kelsie Thu ⁸

John Soong ¹⁰

Shu-Chuan Lin ¹⁰

Angela Hsin Chin Tsai ¹

Tomo Osako ¹

Teresa Algara ¹

D. N. Saunders ¹

Jason Wong ¹

Xian Jian ¹¹

Marcel B Bally ⁷

James D. Brenton ¹¹

Grant W. Brown ⁵

Sohrab P Shah ¹

David Cescon ^{8, 12}

Tak W. Mak ⁸

Carlos CALDAS ¹¹

Peter C Stirling ⁴

Phil Hieter ⁶

Shankar Balasubramanian ^{2, 3}

SAMUEL R. APARICIO ¹

Hide authors affiliations Show authors affiliations: 12 affiliations

Department of Molecular Oncology, and Department of Pathology and Laboratory Medicine, British Columbia Cancer Research Centre, University of British Columbia, Vancouver, Canada |

Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Robinson Way,, Cambridge, UK |

Department of Chemistry, University of Cambridge, Cambridge, UK |

⁴

Terry Fox laboratory, BC Cancer Agency, Vancouver, Canada |

⁵

Department of Biochemistry and Donnelly Centre, University of Toronto, Toronto, Canada |

⁶

Michael Smith Laboratories, University of British Columbia, Vancouver, Canada |

⁷

BC Cancer Agency and Department of Pathology and Laboratory Medicine, Advanced Therapeutics, University of British Columbia, Vancouver, Canada |

⁸

Campbell Family Institute for Breast Cancer Research, Princess Margret Cancer Centre, Toronto, Canada |

⁹

Department of Integrative Oncology, BC Cancer Agency, Vancouver, Canada |

¹⁰

Senhwa Biosciences, Inc., New Taipei City |

¹¹

Cancer Research UK Cambridge Research Institute and Department of Oncology, University of Cambridge, Li Ka Shing Centre, Cambridge, UK |

¹²

Division of Medical Oncology and Hematology, Department of Medicine, University of Toronto, Toronto, Canada |

Publication type: Journal Article

Publication date: 2017-02-17

Springer Nature

Journal: Nature Communications

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Quartile WOS

Impact factor: 16.6

ISSN: 20411723, 20411723

DOI: 10.1038/ncomms14432

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PubMed ID: 28211448

General Chemistry

General Biochemistry, Genetics and Molecular Biology

General Physics and Astronomy

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). Stabilization of DNA quadruplex structures (G4) is lethal for cells with a compromised DNA repair pathway. Here, the authors show that CX-5461, a small molecule in clinical trials as RNA polymerase inhibitor, has G4-stablization properties and can be repurposed to target DNA repair-defective cancers cells.

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Xu H. et al. CX-5461 is a DNA G-quadruplex stabilizer with selective lethality in BRCA1/2 deficient tumours // Nature Communications. 2017. Vol. 8. No. 1. 14432

GOST all authors (up to 50) Copy

Xu H., Di Antonio M., McKinney S., Mathew V., Ho B., Oneil N. J., Santos N. D., Silvester J., Wei V., Garcia J., Kabeer F., Lai D., Soriano P., Banáth J., Chiu D. S., Yap D. B., Le D. D., Ye F. B., Zhang A., Thu K., Soong J., Lin S., Tsai A. H. C., Osako T., Algara T., Saunders D. N., Wong J., Jian X., Bally M. B., Brenton J. D., Brown G. W., Shah S. P., Cescon D., Mak T. W., CALDAS C., Stirling P. C., Hieter P., Balasubramanian S., APARICIO S. R. CX-5461 is a DNA G-quadruplex stabilizer with selective lethality in BRCA1/2 deficient tumours // Nature Communications. 2017. Vol. 8. No. 1. 14432

RIS |

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RIS Copy

TY - JOUR

DO - 10.1038/ncomms14432

UR - https://doi.org/10.1038/ncomms14432

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

T2 - Nature Communications

AU - Xu, Hong

AU - Di Antonio, Marco

AU - McKinney, Steven

AU - Mathew, Veena

AU - Ho, Brandon

AU - Oneil, Nigel J

AU - Santos, Nancy Dos

AU - Silvester, Jennifer

AU - Wei, Vivien

AU - Garcia, Jessica

AU - Kabeer, Farhia

AU - Lai, Daniel

AU - Soriano, Priscilla

AU - Banáth, Judit

AU - Chiu, Derek S.

AU - Yap, Damian B.S.

AU - Le, Daniel D

AU - Ye, Frank B

AU - Zhang, Anni

AU - Thu, Kelsie

AU - Soong, John

AU - Lin, Shu-Chuan

AU - Tsai, Angela Hsin Chin

AU - Osako, Tomo

AU - Algara, Teresa

AU - Saunders, D. N.

AU - Wong, Jason

AU - Jian, Xian

AU - Bally, Marcel B

AU - Brenton, James D.

AU - Brown, Grant W.

AU - Shah, Sohrab P

AU - Cescon, David

AU - Mak, Tak W.

AU - CALDAS, Carlos

AU - Stirling, Peter C

AU - Hieter, Phil

AU - Balasubramanian, Shankar

AU - APARICIO, SAMUEL R.

PY - 2017

DA - 2017/02/17

PB - Springer Nature

IS - 1

VL - 8

PMID - 28211448

SN - 2041-1723

ER -

BibTex

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BibTex Copy

@article{2017_Xu,

author = {Hong Xu and Marco Di Antonio and Steven McKinney and Veena Mathew and Brandon Ho and Nigel J Oneil and Nancy Dos Santos and Jennifer Silvester and Vivien Wei and Jessica Garcia and Farhia Kabeer and Daniel Lai and Priscilla Soriano and Judit Banáth and Derek S. Chiu and Damian B.S. Yap and Daniel D Le and Frank B Ye and Anni Zhang and Kelsie Thu and John Soong and Shu-Chuan Lin and Angela Hsin Chin Tsai and Tomo Osako and Teresa Algara and D. N. Saunders and Jason Wong and Xian Jian and Marcel B Bally and James D. Brenton and Grant W. Brown and Sohrab P Shah and David Cescon and Tak W. Mak and Carlos CALDAS and Peter C Stirling and Phil Hieter and Shankar Balasubramanian and SAMUEL R. APARICIO},

title = {CX-5461 is a DNA G-quadruplex stabilizer with selective lethality in BRCA1/2 deficient tumours},

journal = {Nature Communications},

year = {2017},

volume = {8},

publisher = {Springer Nature},

month = {feb},

url = {https://doi.org/10.1038/ncomms14432},

number = {1},

doi = {10.1038/ncomms14432}

}

Found error?

Publisher

Springer Nature

Journal

Nature Communications

Quartile SCImago

Quartile WOS

Impact factor

16.6

ISSN

20411723 (Print)
20411723 (Electronic)