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

• Published in: Gynecologic oncology Vol. 133; no. 3; pp. 591 - 598
• Main Authors: Alkema, N.G, Tomar, T, van der Zee, A.G.J, Everts, M, Meersma, G.J, Hollema, H, de Jong, S, van Vugt, M.A.T.M, Wisman, G.B.A
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2014
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Ataxia Telangiectasia Mutated Proteins; Cell Cycle Checkpoints - drug effects; Cell Cycle Checkpoints - genetics; Cell Line, Tumor; Cell Survival - drug effects; Checkpoint Kinase 2 - genetics; Checkpoint Kinase 2 - metabolism; Chemoresistance; Chk2; Cisplatin - pharmacology; Cisplatin - therapeutic use; Cohort Studies; Cystadenocarcinoma, Serous - drug therapy; Cystadenocarcinoma, Serous - metabolism; Cystadenocarcinoma, Serous - pathology; DNA Damage - physiology; DNA damage response; DNA Repair - physiology; DNA, Neoplasm; Drug Resistance, Neoplasm - genetics; Drug Resistance, Neoplasm - physiology; Female; Gene Knockdown Techniques; Hematology, Oncology and Palliative Medicine; Humans; Middle Aged; Neoplasm Grading; Obstetrics and Gynecology; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Platinum-based chemotherapy; Prognosis; Signal Transduction; Treatment Outcome; Young Adult; Chk2; DNA damage response; Platinum-based chemotherapy; Chemoresistance; Ovarian cancer
• ISSN: 0090-8258; 1095-6859
• DOI: 10.1016/j.ygyno.2014.03.557

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.