N G Alkema1, T Tomar1, A G J van der Zee1, M Everts2, G J Meersma2, H Hollema3, S de Jong2, M A T M van Vugt4, G B A Wisman5. 1. Department of Gynecologic Oncology, University Medical Centre Groningen, University of Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands. 2. Department of Medical Oncology, University Medical Centre Groningen, University of Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands. 3. Department of Pathology, University Medical Centre Groningen, University of Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands. 4. Department of Medical Oncology, University Medical Centre Groningen, University of Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands. Electronic address: m.vugt@umcg.nl. 5. Department of Gynecologic Oncology, University Medical Centre Groningen, University of Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands. Electronic address: g.b.a.wisman@umcg.nl.
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.
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.
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Authors: My Linh Thibodeau; Caralyn Reisle; Eric Zhao; Lee Ann Martin; Yazeed Alwelaie; Karen L Mungall; Carolyn Ch'ng; Ruth Thomas; Tony Ng; Stephen Yip; Howard J Lim; Sophie Sun; Sean S Young; Aly Karsan; Yongjun Zhao; Andrew J Mungall; Richard A Moore; Daniel J Renouf; Karen Gelmon; Yussanne P Ma; Malcolm Hayes; Janessa Laskin; Marco A Marra; Kasmintan A Schrader; Steven J M Jones Journal: Cold Spring Harb Mol Case Stud Date: 2017-09-01