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Checkpoint kinase 2 (Chk2) supports sensitivity to platinum-based treatment in high grade serous ovarian cancer

  • Author Footnotes
    1 These authors contributed equally.
    N.G. Alkema
    Footnotes
    1 These authors contributed equally.
    Affiliations
    Department of Gynecologic Oncology, University Medical Centre Groningen, University of Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands
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  • Author Footnotes
    1 These authors contributed equally.
    T. Tomar
    Footnotes
    1 These authors contributed equally.
    Affiliations
    Department of Gynecologic Oncology, University Medical Centre Groningen, University of Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands
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  • A.G.J. van der Zee
    Affiliations
    Department of Gynecologic Oncology, University Medical Centre Groningen, University of Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands
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  • M. Everts
    Affiliations
    Department of Medical Oncology, University Medical Centre Groningen, University of Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands
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  • G.J. Meersma
    Affiliations
    Department of Medical Oncology, University Medical Centre Groningen, University of Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands
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  • H. Hollema
    Affiliations
    Department of Pathology, University Medical Centre Groningen, University of Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands
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  • S. de Jong
    Affiliations
    Department of Medical Oncology, University Medical Centre Groningen, University of Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands
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  • Author Footnotes
    2 These authors contributed equally.
    M.A.T.M. van Vugt
    Correspondence
    Corresponding authors. Fax: +31 50 3611806.
    Footnotes
    2 These authors contributed equally.
    Affiliations
    Department of Medical Oncology, University Medical Centre Groningen, University of Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands
    Search for articles by this author
  • Author Footnotes
    2 These authors contributed equally.
    G.B.A. Wisman
    Correspondence
    Corresponding authors. Fax: +31 50 3611806.
    Footnotes
    2 These authors contributed equally.
    Affiliations
    Department of Gynecologic Oncology, University Medical Centre Groningen, University of Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally.
    2 These authors contributed equally.

      Highlights

      • High Chk2 expression is related to better response to platinum-based chemotherapy.
      • Chk2 depletion abrogated cisplatin-induced S-phase arrest and caused resistance to cisplatin in long-term survival assays in ovarian cancer cells.
      • Chk2 inhibitors should not be added to platinum-based chemotherapy in ovarian cancer.

      Abstract

      Objective

      Platinum-based chemotherapy is the standard treatment in advanced stage high grade serous ovarian cancer (HGSOC), but the majority of patients will relapse with drug-resistant disease. Platinum induces double-strand DNA breaks and subsequently activation of the DNA damage response (DDR). Drugs targeting DDR pathway components have gained major interest to be combined with chemotherapy as they could increase the therapeutic window. In the present study, we investigated the activation status of the Ataxia Telangiectasia Mutated (ATM) signaling axis within the DDR in a large, well-defined cohort of advanced stage HGSOC patients.

      Methods

      Pre-therapy activation status of the ATM signaling axis of the DDR was determined by immunohistochemistry in 125 chemo-naive advanced stage HGSOC patients. Ovarian cancer cell lines with stable checkpoint kinase 2 (Chk2) knock down were used to study cell cycle distribution and survival in long-term clonogenic survival assays.

      Results

      All ATM signaling axis components showed high expression levels. In two well-defined groups with the largest contrast in treatment response, high expression of Chk2 was related to good response (OR = 0.132; P = 0.014). Chk2 depletion abrogated the cisplatin-induced S-phase cell cycle arrest and caused increased resistance to cisplatin in long-term clonogenic survival assays.

      Conclusions

      Chk2 is related to good response to platinum-based chemotherapy in advanced stage HGSOC patients. Chk2-depleted ovarian cancer cell lines have diminished platinum sensitivity, suggesting that Chk2 should not be considered a therapeutic target along with platinum-based treatment in HGSOC patients.

      Keywords

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