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ERCC1-XPF deficiency is a predictor of olaparib induced synthetic lethality and platinum sensitivity in epithelial ovarian cancers.
- Source :
-
Gynecologic oncology [Gynecol Oncol] 2019 May; Vol. 153 (2), pp. 416-424. Date of Electronic Publication: 2019 Feb 21. - Publication Year :
- 2019
-
Abstract
- Purpose: PARP inhibitor maintenance therapy in platinum sensitive sporadic ovarian cancers improves progression free survival. However, biomarker for synthetic lethality in platinum sensitive sporadic disease is yet to be defined. ERCC1-XPF heterodimer is a key player in nucleotide excision repair (NER) involved in the repair of platinum induced DNA damage. In the current study, we tested whether ERCC1-XPF deficiency would predict synthetic lethality to the PARP inhibitor Olaparib and platinum sensitivity in ovarian cancers.<br />Methods: ERCC1, XPF and PARP1 protein expression was evaluated in tumors from a cohort of 331 patients treated at Nottingham University Hospitals and correlated to clinicopathological features and survival. Pre-clinically, ERCC1 and XPF was depleted in A2780 (platinum sensitive) and A2780cis (platinum resistant) ovarian cancer cell lines and tested for platinum sensitivity as well as for Olaparib induced synthetic lethality.<br />Results: Low ERCC1 was significantly associated with improved progression free survival (PFS) in patients with ovarian cancers in univariate (p = 0.001) and multivariate (p = 0.002) analysis. In addition, low ERCC1/low XPF (p = 0.003) or low ERCC1/low PARP1 (p = 0.0001) tumors was also linked to better PFS compared to high ERCC1/high XPF or high ERCC1/high PARP1 tumors. Pre-clinically, ERCC1 or XPF depletion not only increased platinum sensitivity but also increased toxicity to Olaparib therapy. Increased sensitivity was associated with DNA double strand breaks (DSBs) accumulation, cell cycle arrest and increased apoptosis.<br />Conclusion: The data provide evidence that low ERCC1 is not only a predictor of platinum sensitivity but is also a promising biomarker for Olaparib induced synthetic lethality in ovarian cancers.<br /> (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Subjects :
- Carcinoma, Ovarian Epithelial genetics
Cell Line, Tumor
DNA-Binding Proteins biosynthesis
DNA-Binding Proteins genetics
Endonucleases biosynthesis
Endonucleases genetics
Female
Humans
Immunohistochemistry
Poly (ADP-Ribose) Polymerase-1 antagonists & inhibitors
Poly (ADP-Ribose) Polymerase-1 biosynthesis
Poly(ADP-ribose) Polymerase Inhibitors pharmacology
RNA, Small Interfering administration & dosage
RNA, Small Interfering genetics
Tissue Array Analysis
Transfection
Carcinoma, Ovarian Epithelial drug therapy
Carcinoma, Ovarian Epithelial metabolism
DNA-Binding Proteins deficiency
Endonucleases deficiency
Organoplatinum Compounds pharmacology
Phthalazines pharmacology
Piperazines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1095-6859
- Volume :
- 153
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Gynecologic oncology
- Publication Type :
- Academic Journal
- Accession number :
- 30797591
- Full Text :
- https://doi.org/10.1016/j.ygyno.2019.02.014