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Progression through mitosis promotes PARP inhibitor-induced cytotoxicity in homologous recombination-deficient cancer cells

Author

Listed:
  • Pepijn M. Schoonen

    (University Medical Center Groningen, University of Groningen)

  • Francien Talens

    (University Medical Center Groningen, University of Groningen)

  • Colin Stok

    (University Medical Center Groningen, University of Groningen)

  • Ewa Gogola

    (The Netherlands Cancer Institute)

  • Anne Margriet Heijink

    (University Medical Center Groningen, University of Groningen)

  • Peter Bouwman

    (The Netherlands Cancer Institute)

  • Floris Foijer

    (European Research Institute for the Biology of Ageing, University of Groningen University Medical Center Groningen)

  • Madalena Tarsounas

    (The CRUK/MRC Oxford Institute)

  • Sohvi Blatter

    (Institute of Animal Pathology, Vetsuisse Faculty, University of Bern)

  • Jos Jonkers

    (The Netherlands Cancer Institute)

  • Sven Rottenberg

    (Institute of Animal Pathology, Vetsuisse Faculty, University of Bern)

  • Marcel A. T. M. van Vugt

    (University Medical Center Groningen, University of Groningen)

Abstract

Mutations in homologous recombination (HR) genes BRCA1 and BRCA2 predispose to tumorigenesis. HR-deficient cancers are hypersensitive to Poly (ADP ribose)-polymerase (PARP) inhibitors, but can acquire resistance and relapse. Mechanistic understanding how PARP inhibition induces cytotoxicity in HR-deficient cancer cells is incomplete. Here we find PARP inhibition to compromise replication fork stability in HR-deficient cancer cells, leading to mitotic DNA damage and consequent chromatin bridges and lagging chromosomes in anaphase, frequently leading to cytokinesis failure, multinucleation and cell death. PARP-inhibitor-induced multinucleated cells fail clonogenic outgrowth, and high percentages of multinucleated cells are found in vivo in remnants of PARP inhibitor-treated Brca2−/−;p53−/− and Brca1−/−;p53−/− mammary mouse tumours, suggesting that mitotic progression promotes PARP-inhibitor-induced cell death. Indeed, enforced mitotic bypass through EMI1 depletion abrogates PARP-inhibitor-induced cytotoxicity. These findings provide insight into the cytotoxic effects of PARP inhibition, and point at combination therapies to potentiate PARP inhibitor treatment of HR-deficient tumours.

Suggested Citation

  • Pepijn M. Schoonen & Francien Talens & Colin Stok & Ewa Gogola & Anne Margriet Heijink & Peter Bouwman & Floris Foijer & Madalena Tarsounas & Sohvi Blatter & Jos Jonkers & Sven Rottenberg & Marcel A. , 2017. "Progression through mitosis promotes PARP inhibitor-induced cytotoxicity in homologous recombination-deficient cancer cells," Nature Communications, Nature, vol. 8(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15981
    DOI: 10.1038/ncomms15981
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    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. Jun Dai & Shuyu Zheng & Matías M. Falco & Jie Bao & Johanna Eriksson & Sanna Pikkusaari & Sofia Forstén & Jing Jiang & Wenyu Wang & Luping Gao & Fernando Perez-Villatoro & Olli Dufva & Khalid Saeed & , 2024. "Tracing back primed resistance in cancer via sister cells," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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