Beta-catenin mutations in hepatocellular cancer, tumor cell metabolism, and the response of these tumors to mTOR inhibition.

Abstract

583 Background: Hepatocellular cancer (HCC) continues to grow in incidence despite approval of many new therapies including immune checkpoint inhibitors (ICIs) and TKIs. Genomic landscape of HCC is becoming increasing apparent through WGS and WES. One major driver of HCC is the Wnt/b-catenin pathway. Mutations in CTNNB1, which encodes for b-catenin, are evident in 26-37% of all human HCCs. However, expression of mutant-b-catenin in liver in mice is insufficient for HCC development. Indeed, analysis of HCC cases has revealed CTNNB1 mutations to significantly co-exist with other aberrations including activation/overexpression of Met and Myc and mutations in TERT promoter or mutations in NFE2L2/KEAP1, APOB and ARID2. Methods: Using sleeping beauty transposon/transposase and hydrodynamic tail vein injection, we co-expressed mutant-CTNNB1 (S45Y, S33Y or T41A) and one other clinically relevant co-occurrence to study significance and biology of HCC. Any novel findings in the preclinical model were validated in HCC patient cohorts. Results: Co-expression of mutant-CTNNB1 and one relevant co-occurrence led to development of HCC in mice in 6-10 weeks. All HCC in these models showed a dramatic increase in glutamine synthetase (GS), encoded by Glul, a known target of the Wnt/b-catenin signaling pathway in the liver. This led to an increase in glutamine levels in the tumor-bearing livers. Increased glutamine in the tumors in turn led to increased levels of phospho-mTOR-S2448, a marker of mTORC1 activation. In fact, examination of ~400 patient HCCs showed a significant correlation between positive GS and p-mTOR-S2448 staining. Treatment of Met-b-catenin model with Rapamycin led to notable and significant decrease in HCC burden. Conclusions: Our studydemonstrates b-catenin-mutated HCC to be positive for both GS and in turn mTORC1 active. This provides a novel opportunity for personalized medicine in HCC and CTNNB1-mutated HCCs may be vulnerable to therapeutic targeting by mTOR and more specially, mTORC1 inhibitors.