Research Assistant Professor The University of Hong Kong The University of Hong Kong, Hong Kong
Abstract: In recent years, multiple drugs have been approved for the treatment of hepatocellular carcinoma (HCC). However, the clinical benefit is far from optimal, extending the survival of patients for a few months only. This is due to the complex, heterogeneous nature of different HCC patients, in which cancer cells harbor a mix of driver and passenger mutations. Traditional cell lines and animal models lack a clean background in which the effects of individual driver mutations can be studied in detail in the absence of passenger mutations. Here, we utilized HCC tumors generated by the hydrodynamic tail vein injection of proto-oncogene combinations in mice together with the tumor organoid platform to study the characteristics of HCC driven by different driver mutations and their response to therapeutics. We have successfully established HCC tumor organoids with specific driver mutations (loss of TP53, Axin1, and PTEN, and CTNNB1 activating mutation in the background of MYC overexpression) and validated their gene mutations at both genomic and proteomic levels. Using a high-throughput screening approach, with the screen consisting of over 600 FDA-approved drugs for drug repurposing, we have identified ERBB family inhibitors as therapeutic targets for CTNNB1 mutation-driven HCC (Δ90CTNNB1/MYC). Multi-omics analysis through chromatin accessibility, transcriptomics, and phosphoproteomics revealed activation of the ERBB signaling pathway in Δ90CTNNB1/MYC models via increase transcription of related genes, Egft and Tgfa, and phosphorylation of ERBB family, EGFR and ERBB2. Activation of this pathway in HCC patients with CTNNB1 activating mutation was further confirmed with clinical data extracted from publicly available datasets. Finally, the sensitivity of CTNNB1 mutation-driven HCC towards ERBB family inhibitors was validated using an animal model. In conclusion, we successfully established an HCC organoid platform with specific driver mutations and discovered a novel therapeutic target for CTNNB1 mutation-driven HCC. We further elucidated the distinct pathways that potentially drive the sensitivity towards ERBB family inhibitors in CTNNB1 mutation-driven HCC. Our findings provide the foundation for future repurposing of FDA-approved drugs for the treatment of HCC patients with CTNNB1 mutation.
Funding Source: This project is supported by Research Grants Council of Hong Kong - Research Impact Fund 2020/21 (R7022-20F), Research Fellow Scheme (RFS2122-7S05) and Croucher Foundation – Croucher Senior Research Fellowship to Stephanie Ma.
