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ERCC1-XPF deficiency is a predictor of olaparib induced synthetic lethality and platinum sensitivity in epithelial ovarian cancers

  • Katia A. Mesquita
    Affiliations
    Translational Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham University Hospitals, Nottingham NG5 1PB, UK
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  • Muslim Alabdullah
    Affiliations
    Translational Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham University Hospitals, Nottingham NG5 1PB, UK

    Department of Pathology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham NG51PB, UK
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  • Michaela Griffin
    Affiliations
    Translational Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham University Hospitals, Nottingham NG5 1PB, UK
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  • Michael S. Toss
    Affiliations
    Department of Pathology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham NG51PB, UK
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  • Tarek M.A. Abdel Fatah
    Affiliations
    Department of Oncology, Nottingham University Hospitals, City Hospital Campus, Nottingham NG5 1PB, UK
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  • Adel Alblihy
    Affiliations
    Translational Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham University Hospitals, Nottingham NG5 1PB, UK
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  • Paul Moseley
    Affiliations
    Department of Oncology, Nottingham University Hospitals, City Hospital Campus, Nottingham NG5 1PB, UK
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  • Stephen Y.T. Chan
    Affiliations
    Department of Oncology, Nottingham University Hospitals, City Hospital Campus, Nottingham NG5 1PB, UK
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  • Emad A. Rakha
    Affiliations
    Department of Pathology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham NG51PB, UK
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  • Srinivasan Madhusudan
    Correspondence
    Corresponding author at: Translational Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham University Hospitals, Nottingham NG51PB, UK.
    Affiliations
    Translational Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham University Hospitals, Nottingham NG5 1PB, UK

    Department of Oncology, Nottingham University Hospitals, City Hospital Campus, Nottingham NG5 1PB, UK
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Published:February 21, 2019DOI:https://doi.org/10.1016/j.ygyno.2019.02.014

      Highlights

      • PARP inhibitor therapy improves progression free survival in platinum sensitive ovarian cancers.
      • Robust biomarker to predict benefit from PARP inhibitor therapy in sporadic tumors is yet to be established.
      • Here we show that ERCC1-XPF deficiency predicts platinum sensitivity.
      • ERCC1 or XPF deficient ovarian cancer cells are sensitive to PARP inhibitor Olaparib through synthetic lethality.

      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.

      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.

      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.

      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.

      Keywords

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