IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v12y2021i1d10.1038_s41467-021-23463-8.html
   My bibliography  Save this article

Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance

Author

Listed:
  • Diana Zatreanu

    (The Institute of Cancer Research
    The Institute of Cancer Research)

  • Helen M. R. Robinson

    (The Glenn Berge Building, Babraham Research Campus)

  • Omar Alkhatib

    (The Glenn Berge Building, Babraham Research Campus)

  • Marie Boursier

    (The Glenn Berge Building, Babraham Research Campus)

  • Harry Finch

    (The Glenn Berge Building, Babraham Research Campus)

  • Lerin Geo

    (The Glenn Berge Building, Babraham Research Campus)

  • Diego Grande

    (The Glenn Berge Building, Babraham Research Campus)

  • Vera Grinkevich

    (The Glenn Berge Building, Babraham Research Campus)

  • Robert A. Heald

    (The Glenn Berge Building, Babraham Research Campus)

  • Sophie Langdon

    (The Glenn Berge Building, Babraham Research Campus)

  • Jayesh Majithiya

    (The Glenn Berge Building, Babraham Research Campus)

  • Claire McWhirter

    (The Glenn Berge Building, Babraham Research Campus)

  • Niall M. B. Martin

    (The Glenn Berge Building, Babraham Research Campus)

  • Shaun Moore

    (The Glenn Berge Building, Babraham Research Campus)

  • Joana Neves

    (The Glenn Berge Building, Babraham Research Campus)

  • Eeson Rajendra

    (The Glenn Berge Building, Babraham Research Campus)

  • Marco Ranzani

    (The Glenn Berge Building, Babraham Research Campus)

  • Theresia Schaedler

    (The Glenn Berge Building, Babraham Research Campus)

  • Martin Stockley

    (The Glenn Berge Building, Babraham Research Campus)

  • Kimberley Wiggins

    (The Glenn Berge Building, Babraham Research Campus)

  • Rachel Brough

    (The Institute of Cancer Research
    The Institute of Cancer Research)

  • Sandhya Sridhar

    (The Institute of Cancer Research
    The Institute of Cancer Research)

  • Aditi Gulati

    (The Institute of Cancer Research
    The Institute of Cancer Research)

  • Nan Shao

    (The Institute of Cancer Research
    The Institute of Cancer Research)

  • Luned M. Badder

    (The Breast Cancer Now Research Unit, King’s College London)

  • Daniela Novo

    (The Institute of Cancer Research)

  • Eleanor G. Knight

    (The Institute of Cancer Research)

  • Rebecca Marlow

    (The Institute of Cancer Research
    The Breast Cancer Now Research Unit, King’s College London)

  • Syed Haider

    (The Institute of Cancer Research)

  • Elsa Callen

    (National Cancer Institute, NIH)

  • Graeme Hewitt

    (The Francis Crick Institute)

  • Joost Schimmel

    (Leiden University Medical Center)

  • Remko Prevo

    (University of Oxford, Old Road Campus Research Building, Roosevelt Drive)

  • Christina Alli

    (Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus)

  • Amanda Ferdinand

    (Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus)

  • Cameron Bell

    (Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus)

  • Peter Blencowe

    (Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus)

  • Chris Bot

    (Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus)

  • Mathew Calder

    (Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus)

  • Mark Charles

    (Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus)

  • Jayne Curry

    (Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus)

  • Tennyson Ekwuru

    (Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus)

  • Katherine Ewings

    (Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus)

  • Wojciech Krajewski

    (Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus)

  • Ellen MacDonald

    (Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus)

  • Hollie McCarron

    (Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus)

  • Leon Pang

    (Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus)

  • Chris Pedder

    (Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus)

  • Laurent Rigoreau

    (Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus)

  • Martin Swarbrick

    (Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus)

  • Ed Wheatley

    (Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus)

  • Simon Willis

    (Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus)

  • Ai Ching Wong

    (Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus)

  • Andre Nussenzweig

    (National Cancer Institute, NIH)

  • Marcel Tijsterman

    (Leiden University Medical Center)

  • Andrew Tutt

    (The Institute of Cancer Research
    The Breast Cancer Now Research Unit, King’s College London)

  • Simon J. Boulton

    (The Glenn Berge Building, Babraham Research Campus
    The Francis Crick Institute)

  • Geoff S. Higgins

    (University of Oxford, Old Road Campus Research Building, Roosevelt Drive)

  • Stephen J. Pettitt

    (The Institute of Cancer Research
    The Institute of Cancer Research)

  • Graeme C. M. Smith

    (The Glenn Berge Building, Babraham Research Campus)

  • Christopher J. Lord

    (The Institute of Cancer Research
    The Institute of Cancer Research)

Abstract

To identify approaches to target DNA repair vulnerabilities in cancer, we discovered nanomolar potent, selective, low molecular weight (MW), allosteric inhibitors of the polymerase function of DNA polymerase Polθ, including ART558. ART558 inhibits the major Polθ-mediated DNA repair process, Theta-Mediated End Joining, without targeting Non-Homologous End Joining. In addition, ART558 elicits DNA damage and synthetic lethality in BRCA1- or BRCA2-mutant tumour cells and enhances the effects of a PARP inhibitor. Genetic perturbation screening revealed that defects in the 53BP1/Shieldin complex, which cause PARP inhibitor resistance, result in in vitro and in vivo sensitivity to small molecule Polθ polymerase inhibitors. Mechanistically, ART558 increases biomarkers of single-stranded DNA and synthetic lethality in 53BP1-defective cells whilst the inhibition of DNA nucleases that promote end-resection reversed these effects, implicating these in the synthetic lethal mechanism-of-action. Taken together, these observations describe a drug class that elicits BRCA-gene synthetic lethality and PARP inhibitor synergy, as well as targeting a biomarker-defined mechanism of PARPi-resistance.

Suggested Citation

  • Diana Zatreanu & Helen M. R. Robinson & Omar Alkhatib & Marie Boursier & Harry Finch & Lerin Geo & Diego Grande & Vera Grinkevich & Robert A. Heald & Sophie Langdon & Jayesh Majithiya & Claire McWhirt, 2021. "Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23463-8
    DOI: 10.1038/s41467-021-23463-8
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-021-23463-8
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-021-23463-8?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Anne Margriet Heijink & Colin Stok & David Porubsky & Eleni Maria Manolika & Jurrian K. Kanter & Yannick P. Kok & Marieke Everts & H. Rudolf Boer & Anastasia Audrey & Femke J. Bakker & Elles Wierenga , 2022. "Sister chromatid exchanges induced by perturbed replication can form independently of BRCA1, BRCA2 and RAD51," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Jeffrey Patterson-Fortin & Heta Jadhav & Constantia Pantelidou & Tin Phan & Carter Grochala & Anita K. Mehta & Jennifer L. Guerriero & Gerburg M. Wulf & Brian M. Wolpin & Ben Z. Stanger & Andrew J. Ag, 2023. "RETRACTED ARTICLE: Polymerase θ inhibition activates the cGAS-STING pathway and cooperates with immune checkpoint blockade in models of BRCA-deficient cancer," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    3. Elena Giudice & Tzu-Ting Huang & Jayakumar R. Nair & Grant Zurcher & Ann McCoy & Darryl Nousome & Marc R. Radke & Elizabeth M. Swisher & Stanley Lipkowitz & Kristen Ibanez & Duncan Donohue & Tyler Mal, 2024. "The CHK1 inhibitor prexasertib in BRCA wild-type platinum-resistant recurrent high-grade serous ovarian carcinoma: a phase 2 trial," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    4. Megan E. Luedeman & Susanna Stroik & Wanjuan Feng & Adam J. Luthman & Gaorav P. Gupta & Dale A. Ramsden, 2022. "Poly(ADP) ribose polymerase promotes DNA polymerase theta-mediated end joining by activation of end resection," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    5. Diana Rubio-Contreras & Fernando Gómez-Herreros, 2023. "TDP1 suppresses chromosomal translocations and cell death induced by abortive TOP1 activity during gene transcription," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    6. Aldo S. Bader & Martin Bushell, 2023. "iMUT-seq: high-resolution DSB-induced mutation profiling reveals prevalent homologous-recombination dependent mutagenesis," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23463-8. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.