Abstract 1628: Tumor cell specific inhibition of oncogenic Wnt signaling

Abstract Aberrant activation of the Wnt/β-catenin pathway is one of the most frequent signaling abnormalities known in human cancer and contributes to both tumor initiation and tumor maintenance. In normal tissues, however, the Wnt/β-catenin pathway plays widespread and important roles in the regulation of stem cell behavior, differentiation, and homeostasis. Consequently, a challenge in developing strategies for antagonizing Wnt signaling in cancer will be to minimize harmful side-effects on normal tissues. In many human cancers the canonical Wnt pathway is activated by single base missense mutations in β-catenin located near N-terminal phosphorylation sites that control the protein's stability. These mutant forms of β-catenin represent targets that are unique to cancer cells. We have screened RNAi reagents designed specifically to target individual mutant β-catenin sequences found in cancer cells while having minimal impact on wild-type β-catenin. We have used colorectal and hepatoma cell lines with defined β-catenin mutations for initial evaluation of the efficacy and specificity of knock-down, in conjunction with signaling assays based on nuclear accumulation of β-catenin and TCF-responsive reporter assays. We find that mutation-specific siRNA or shRNA reagents can be identified that substantially reduce β-catenin levels in cancer cells bearing the respective mutation, but have little or no effect on cells that are wild-type for β-catenin or which carry a different mutation. We also observe mutation-specific inhibitory effects on cell growth. These results provide encouragement for developing this strategy as a means of silencing oncogenic mutations in cancer while causing only minimal collateral damage to normal tissues. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1628.