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

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