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

Pepijn M. Schoonen, Francien Talens, Colin Stok, Ewa Gogola, Anne Margriet Heijink, Peter Bouwman, Floris Foijer, Madalena Tarsounas, Sohvi Blatter, Jos Jonkers, Sven Rottenberg and Marcel A. T. M. van Vugt ()
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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

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms15981

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