Complete response of Ctnnb1-mutated tumours to β-catenin suppression by locked nucleic acid antisense in a mouse hepatocarcinogenesis model

Background & Aims: Hepatocellular cancer (HCC) remains a disease of poor prognosis, highlighting the relevance of elucidating key molecular aberrations that may be targeted for novel therapies. Wnt signalling activation, chiefly due to mutations in CTNNB1, have been identified in a major subset of HCC patients. While several in vitro proof of concept studies show the relevance of suppressing Wnt/beta-catenin signalling in HCC cells or tumour xenograft models, no study has addressed the impact of beta-catenin inhibition in a relevant murine HCC model driven by Ctnnb1 mutations. Methods: We studied the in vivo impact of beta-catenin suppression by locked nucleic acid (LNA) antisense treatment, after establishing Ctnnb1 mutation-driven HCC by diethylnitrosamine and phenobarbital (DEN/PB) administration. Results: The efficacy of LNA directed against beta-catenin vs. scrambled on Wnt signalling was demonstrated in vitro in HCC cells and in vivo in normal mice. The DEN/PB model leads to HCC with Ctnnb1 mutations. A complete therapeutic response in the form of abrogation of HCC was observed after ten treatments of tumour-bearing mice with beta-catenin LNA every 48 h as compared to the scrambled control. A decrease in beta-catenin activity, cell proliferation and increased cell death was evident after beta-catenin suppression. No effect of beta-catenin suppression was evident in non-Ctnnb1 mutated HCC, observed after DEN-only administration. Conclusions: Thus, we provide the in vivo proof of concept that beta-catenin suppression in HCC will be of significant therapeutic benefit, provided the tumours display Wnt activation via mechanisms like CTNNB1 mutations. (C) 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.