Journal Article

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

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

2017

Overview

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. Mutations in BRCA1 and BRCA2 render a cancer cell hypersensitive to PARP inhibitors but they can acquire resistance and relapse. Here the authors find that PARP inhibition leads to replication fork instability, cytokinesis failure and cell death, aiding our understanding of how inhibition leads to cytotoxic outcomes.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/106 / 13/109 / 14/63 / 631/67/1059/602 / 631/80/641/151/2356 / Adenosine diphosphate / Anaphase / Anaphase - drug effects / Animals / Apoptosis / Biocompatibility / BRCA1 protein / BRCA1 Protein - genetics / BRCA2 protein / BRCA2 Protein - genetics / Breast cancer / Breast Neoplasms - drug therapy / Breast Neoplasms - genetics / Bridge failure / Cancer / Cell death / Cell Line, Tumor / Chromatin / Chromosomes / Cytokinesis / Cytokinesis - drug effects / Cytotoxicity / Deoxyribonucleic acid / DNA / DNA damage / DNA Damage - drug effects / Female / HeLa Cells / Homologous recombination / Homology / Humanities and Social Sciences / Humans / Inhibitors / Mammary Neoplasms, Animal - genetics / Mammary Neoplasms, Experimental - genetics / Mice / Mice, Knockout / Mitosis / Mitosis - drug effects / multidisciplinary / Mutation / p53 Protein / Poly(ADP-ribose) polymerase / Poly(ADP-ribose) Polymerase Inhibitors - pharmacology / Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use / Recombinational DNA Repair - genetics / Ribose / Rodents / Science / Science (multidisciplinary) / Targeted cancer therapy / Toxicity / Tumor Suppressor Protein p53 - genetics / Tumor Suppressor Proteins - genetics / Tumorigenesis / Tumors