Cumulative defects in DNA repair pathways drive the PARP inhibitor response in high-grade serous epithelial ovarian cancer cell lines
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Hubert Fleury1,2, Euridice Carmona1,2, Vincent G. Morin1,2, Liliane Meunier1,2, Jean-Yves Masson3,4, Patricia N. Tonin5,6,7, Diane Provencher1,2,8 and Anne-Marie Mes-Masson1,2,9
1Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montreal, Canada
2Institut du cancer de Montréal, Montreal, Canada
3Genome Stability Laboratory, CHU Research Center, Québec City, Canada
4Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University Cancer Research Center, Québec City, Canada
5Cancer Research Program (CRP), The Research Institute of the McGill University Health Centre, Montreal, Canada
6Department of Human Genetics, McGill University, Montreal, Canada
7Department of Medicine, McGill University, Montreal, Canada
8Division of Gynecologic Oncology, Université de Montréal, Montreal, Canada
9Department of Medicine, Université de Montréal, Montreal, Canada
Anne-Marie Mes-Masson, email: firstname.lastname@example.org
Keywords: olaparib, high-grade serous epithelial ovarian cancer, DNA repair pathways, NER, MMR
Received: January 27, 2016 Accepted: June 09, 2016 Published: June 27, 2016
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.
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