Abstract 3383: Inhibition of Akt signaling: a strategy to overcome platinum resistance in ovarian cancer.

Targeted therapies in combination with cytotoxic agents are promising future treatment regimens for women with resistant ovarian cancer. Current standard treatment of serous ovarian cancer is a platinum- (carboplatin) based chemotherapy, usually combined with taxanes. A 90% cure rate is observed in early stage ovarian cancers, however, in advanced stages, about 20-30% of patients never have a remission or will suffer from recurrent disease within 5 years. One major reason is the development of a resistance against the platinum-based chemotherapy. In order to identify possible novel therapeutic targets for platinum-resistant ovarian cancer, we compared gene expression and oncogenic kinase phosphorylation patterns in the human ovarian cancer cell line A2780 and its platinum-resistant variant A2780cis in vitro and in vivo.In vivo, the untreated A2780cis-derived tumor model showed reduced proliferation activity and enhanced apoptosis, while carboplatin treatment failed to induce tumor reduction, as compared to the sensitive A2780-derived tumor model. Analysis of 47 kinase phosphorylation sites in carboplatin-treated A2780 and A2780cis derived tumors revealed that Akt was hyperphosphorylated at Ser273 but not altered during treatment in resistant tumors, whereas Akt phosphorylation was weak and further reduced during treatment in sensitive tumors. This was associated with an unchanged p53 phosphorylation status in resistant tumors during treatment. In line with this, the novel allosteric Akt inhibitor BAY 10001931 resensitized A2780 and A2780cis cells to carboplatin in vitro. To investigate if the Akt phosphorylation status correlated with an activation of downstream targets, RNA of A2780 and A2780cis vehicle- or carboplatin treated tumors was hybridized onto an Illumina Bead Chip array. Here, linear model analysis identified GDF15 as one of four p53-induced target genes possibly involved in the development of chemoresistance. GDF15 protein expression was highly induced during carboplatin treatment in both cell lines, whereas basal GDF15 expression was higher in resistant cells than in sensitive A2780 cells in vitro and in vivo. This was correlated with a higher secretion of GDF15 into the serum of A2780cis-tumor-bearing mice. Similar tendencies were observed in vitro. Interestingly, simultaneous Akt inhibition with BAY 10001931 markedly reduced the carboplatin-induced upregulation of GDF15 in A2780 and A2780cis cells. Additionally, shRNA-mediated knockdown of GDF15 in resistant A2780cis cells also abrogated the phosphorylation of Akt in vitro. These results indicate that a causal relationship exists between Akt activation and GDF15 expression in resistant ovarian cancer cells. Together, a combination treatment with an Akt inhibitor and carboplatin of GDF15-expressing ovarian cancer cells might represent a novel approach to treat resistant ovarian cancer. Citation Format: Julia C. Meier, Bernard Haendler, Anette Sommer, Andrea Hagebarth, Georg Beckmann, Bertolt Kreft, Karl Ziegelbauer, Charlotte C. Kopitz. Inhibition of Akt signaling: a strategy to overcome platinum resistance in ovarian cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3383. doi:10.1158/1538-7445.AM2013-3383