Abstract
Abstract Purpose: Ovarian cancer frequently relapses due to inherent or acquired resistance to platinum-based therapy. To increase therapeutic response, the checkpoint kinases 1 and 2 (CHK1, CHK2) are being targeted in early clinical trials in combination with DNA damaging agents due to their roles in sensing DNA damage and inducing cell cycle arrest. Due to the limited studies on the use of biomarkers to overcome platinum resistance, we set out to characterize potential targets in a cohort of ovarian tumors and paired platinum sensitivity ovarian cancer cell lines. Methods: Total and phospho-protein expression were measured in a panel of 12 ovarian cancer cell lines using antibody arrays in order to characterize signaling pathways. Differentially expressed proteins were measured in a cohort of 128 pre-treatment malignant ovarian tumour lysates using reverse phase protein arrays. Sulforhodamine B cytotoxicity assays were used to assess the DNA damage response relevance of potential targets in paired platinum-sensitive and -resistant ovarian cancer cell lines. Results: Cell line expression clustering identified two groups that differed in patient history: predominantly platinum-based chemotherapy or chemotherapy-naïve background. The overexpressed proteins in the former cluster comprised mainly DNA damage response proteins including p-CHK1 (Ser317) and p-CHK2 (Ser516) implicating these proteins as potential mediators of platinum resistance. Though p-CHK2 had no prognostic value, high p-CHK1 levels were associated with poor overall survival in univariate analysis (medians 21 vs 38 months; corrected P=0.03). In multivariate analysis using a Cox proportional hazard model with other significant factors from univariate analysis (platinum sensitivity, stage, grade, residual disease, and histology), high p-CHK1 tumors had a relative risk of 3.0 (95% CI 1.1 - 8.0, P=0.03), 5.6 for platinum sensitivity (95% CI 2.8-11.1, P<0.001), 1.9 for tumor stage (95% CI 1.2-3.1, P=0.005), and 1.5 for histology (95% CI 1.1-1.9, P=0.004). CHK1 is phosphorylated at Ser317 during DNA damage and accordingly the DNA damage marker p-H2AX (Ser139) was highly expressed in the high p-CHK1 tumor group (P=0.008). The CHK1/2 inhibitor AZD7762 addition had variable effects on the cisplatin dose response when comparing the platinum-sensitive to the paired platinum-resistant cell lines. 50 nM AZD7762 (5.7% growth inhibition) and cisplatin treatment of the platinum resistant PEO4 cells induced a cisplatin concentration response (combination IC50=1.7μM vs cisplatin IC50=9.8μM) similar to that of its paired platinum sensitive PEO1 cell line (cisplatin IC50=2.7μM). Conclusion: This is the first study to identify p-CHK1 as an independent prognostic ovarian cancer biomarker and supports CHK1 as a therapeutic target in platinum-resistant ovarian cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3642. doi:1538-7445.AM2012-3642
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