Oncogenic beta-catenin stimulation of AKT2-CAD-mediated pyrimidine synthesis is targetable vulnerability in liver cancer

CTNNB1, encoding beta-catenin protein, is the most frequently altered proto-oncogene in hepatic neoplasms. In this study, we studied the significance and pathological mechanism of CTNNB1 gain-of-function mutations in hepatocarcinogenesis. Activated beta-catenin not only triggered hepatic tumorigenesis but also exacerbated Tp53 deletion or hepatitis B virus infection-mediated liver cancer development in mouse models. Using untargeted metabolomic profiling, we identified boosted de novo pyrimidine synthesis as the major metabolic aberration in beta-catenin mutant cell lines and livers. Oncogenic beta-catenin transcriptionally stimulated AKT2, which then phosphorylated the rate-limiting de novo pyrimidine synthesis enzyme CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, dihydroorotase) on S1406 and S1859 to potentiate nucleotide synthesis. Moreover, inhibition of beta-catenin/AKT2-stimulated pyrimidine synthesis axis preferentially repressed beta-catenin mutant cell proliferation and tumor formation. Therefore, beta-catenin active mutations are oncogenic in various preclinical liver cancer models. Stimulation of beta-catenin/AKT2/CAD signaling cascade on pyrimidine synthesis is an essential and druggable vulnerability for beta-catenin mutant liver cancer.