Abstract 5037: Sensitivity of ovarian clear cell carcinoma cells to PI3K inhibitors

Abstract

Introduction: Ovarian Clear Cell Carcinoma (OCCC) is generally aggressive and chemoresistant, with five year survival rate of approximately 40%. Recent mutation analysis has indicated a high frequency of PIK3CA mutations, the gene encoding for the p110α subunit in PI3K, in OCCC. Aberrant signaling of the PI3K/AKT pathway might be linked to the aggressiveness of OCCC. In this study, we investigated the sensitivity of ovarian clear cell carcinoma cells with different PIK3CA mutations to inhibitors targeting the PI3K signaling pathway. Experimental design: To elucidate the functional roles of PIK3CA mutations in OCCC, 12 OCCC cell lines carrying PIK3CA wildtype or different PIK3CA mutations were used. By performing WST-1 assay, the IC50 values for cisplatin of the cell lines were compared. Eight stable OCCC cell lines expressing a luciferase reporter fused with a FOXO3a promoter were constructed. FOXO3a is a transcription factor that is exported out of the nucleus by AKT. The difference in the PI3K/AKT pathway activation in these cell lines was then correlated with luciferase activity. PI3K inhibitor LY294002 and dual PI3K/mTOR inhibitor NVP-BEZ235 were used to elucidate the dependency of OCCC cell lines on the PI3K/AKT pathway. Results: When compared with PIK3CA wildtype cell lines, cell lines with PIK3CA mutations K111N, E545K and H1047R had higher IC50 values for cisplatin and PI3K inhibitor LY294002. These 3 cell lines also have lower luciferase activity, indicating increased activation of the PI3K/AKT pathway. The IC50 values for NVP-BEZ235 are similar in PIK3CA wildtype or mutated cell lines. Conclusion: The constitutive activation of the PI3K/AKT pathway in ovarian clear cell carcinoma appears to lead to increased resistance to chemotherapy, possibly by promoting cell survival and inhibiting apoptosis. Inhibition of PI3K/AKT pathway may overcome this resistance. NVP-BEZ235 was shown to be a potent drug in OCCC, it was effective in the nano molar range (IC90 value was reached in all cells lines at drug concentration of 100nM) and was active against PIK3CA mutants. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5037. doi:10.1158/1538-7445.AM2011-5037