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

Schoonen, P. M., Talens, F., Stok, C., Gogola, E., Heijink, A. M., Bouwman, P., Foijer, F., Tarsounas, M., Blatter, S., Jonkers, J., Rottenberg, S. & van Vugt, M. A. T. M., 17-Jul-2017, In : Nature Communications. 8, 13 p., 15981.

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Article number15981
Number of pages13
JournalNature Communications
Volume8
Publication statusPublished - 17-Jul-2017

    Keywords

  • ADP-RIBOSE POLYMERASE, STRAND BREAK REPAIR, FANCONI-ANEMIA, POLY(ADP-RIBOSE) POLYMERASE, BRCA2-DEFICIENT TUMORS, SYNTHETIC LETHALITY, SUSCEPTIBILITY GENE, MAMMARY-TUMORS, FRAGILE SITES, REPLICATION

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