title: Cumulative defects in DNA repair pathways drive the PARP inhibitor response in high-grade serous epithelial ovarian cancer cell lines.
abstract: PARP inhibitors (PARPi), such as Olaparib, have shown promising results in high-grade serous (HGS) epithelial ovarian cancer (EOC) treatment. PARPi sensitivity has been mainly associated with homologous recombination (HR) deficiency, but clinical trials have shown that predicting actual patient response is complex. Here, we investigated gene expression microarray, HR functionality and Olaparib sensitivity of 18 different HGS EOC cell lines and demonstrate that PARPi sensitivity is not only associated with HR defects. Gene target validation show that down regulation of genes in the nucleotide excision repair (NER) and mismatch repair (MMR) pathways (ERCC8 and MLH1, respectively) increases PARPi response. The highest sensitivity was observed when genes in both the HR and either NER or MMR pathways were concomitantly down regulated. Using clinical samples, patients with these concurrent down regulations could be identified. Based on these results, a novel model to predict PARPi sensitivity is herein proposed. This model implies that the extreme responders identified in clinical trials have deficiencies in HR and either NER or MMR.
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Canada.|Institut du cancer de Montréal, Montreal, Canada.
authors.forename: Hubert
authors.initials: H
authors.lastname: Fleury
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Canada.|Institut du cancer de Montréal, Montreal, Canada.
authors.forename: Euridice
authors.initials: E
authors.lastname: Carmona
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Canada.|Institut du cancer de Montréal, Montreal, Canada.
authors.forename: Vincent G
authors.initials: VG
authors.lastname: Morin
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Canada.|Institut du cancer de Montréal, Montreal, Canada.
authors.forename: Liliane
authors.initials: L
authors.lastname: Meunier
authors.affiliation: Genome Stability Laboratory, CHU Research Center, Québec City, Canada.|Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University Cancer Research Center, Québec City, Canada.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Masson
authors.affiliation: Cancer Research Program (CRP), The Research Institute of the McGill University Health Centre, Montreal, Canada.|Department of Human Genetics, McGill University, Montreal, Canada.|Department of Medicine, McGill University, Montreal, Canada.
authors.forename: Patricia N
authors.initials: PN
authors.lastname: Tonin
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Canada.|Institut du cancer de Montréal, Montreal, Canada.|Division of Gynecologic Oncology, Université de Montréal, Montreal, Canada.
authors.forename: Diane
authors.initials: D
authors.lastname: Provencher
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Canada.|Institut du cancer de Montréal, Montreal, Canada.|Department of Medicine, Université de Montréal, Montreal, Canada.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Mes-Masson
mesh_terms: D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D004260:DNA Repair / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D060787:Neoplasm Grading; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010793:Phthalazines / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics
chemical_list: D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C531550:olaparib
keywords: DNA repair pathways; MMR; NER; high-grade serous epithelial ovarian cancer; olaparib