Cumulative defects in DNA repair pathways drive the PARP inhibitor response in high-grade serous epithelial ovarian cancer cell lines
Bibliographic record
Abstract
// Hubert Fleury 1, 2 , Euridice Carmona 1, 2 , Vincent G. Morin 1, 2 , Liliane Meunier 1, 2 , Jean-Yves Masson 3, 4 , Patricia N. Tonin 5, 6, 7 , Diane Provencher 1, 2, 8 and Anne-Marie Mes-Masson 1, 2, 9 1 Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montreal, Canada 2 Institut du cancer de Montréal, Montreal, Canada 3 Genome Stability Laboratory, CHU Research Center, Québec City, Canada 4 Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University Cancer Research Center, Québec City, Canada 5 Cancer Research Program (CRP), The Research Institute of the McGill University Health Centre, Montreal, Canada 6 Department of Human Genetics, McGill University, Montreal, Canada 7 Department of Medicine, McGill University, Montreal, Canada 8 Division of Gynecologic Oncology, Université de Montréal, Montreal, Canada 9 Department of Medicine, Université de Montréal, Montreal, Canada Correspondence to: Anne-Marie Mes-Masson, email: anne-marie.mes-masson@umontreal.ca 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 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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".