title: Checkpoint kinase 2 (Chk2) supports sensitivity to platinum-based treatment in high grade serous 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.
authors.affiliation: Department of Gynecologic Oncology, University Medical Centre Groningen, University of Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands.
authors.forename: N G
authors.initials: NG
authors.lastname: Alkema
authors.affiliation: Department of Gynecologic Oncology, University Medical Centre Groningen, University of Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands.
authors.forename: T
authors.initials: T
authors.lastname: Tomar
authors.affiliation: Department of Gynecologic Oncology, University Medical Centre Groningen, University of Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands.
authors.forename: A G J
authors.initials: AG
authors.lastname: van der Zee
authors.affiliation: Department of Medical Oncology, University Medical Centre Groningen, University of Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Everts
authors.affiliation: Department of Medical Oncology, University Medical Centre Groningen, University of Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands.
authors.forename: G J
authors.initials: GJ
authors.lastname: Meersma
authors.affiliation: Department of Pathology, University Medical Centre Groningen, University of Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Hollema
authors.affiliation: Department of Medical Oncology, University Medical Centre Groningen, University of Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: de Jong
authors.affiliation: 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.
authors.forename: M A T M
authors.initials: MA
authors.lastname: van Vugt
authors.affiliation: 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.
authors.forename: G B A
authors.initials: GB
authors.lastname: Wisman
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D064007:Ataxia Telangiectasia Mutated Proteins; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D064447:Checkpoint Kinase 2 / Q000235:genetics / Q000378:metabolism*; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use*; D015331:Cohort Studies; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004249:DNA Damage / Q000502:physiology; D004260:DNA Repair / Q000502:physiology; D004273:DNA, Neoplasm; D019008:Drug Resistance, Neoplasm / Q000235:genetics / Q000502:physiology*; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D008875:Middle Aged; D060787:Neoplasm Grading; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D015398:Signal Transduction; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D002945:Cisplatin
keywords: Chemoresistance; Chk2; DNA damage response; Ovarian cancer; Platinum-based chemotherapy