Interactions between driver genes shape the signaling pathway landscape and direct hepatocellular carcinoma therapy.

Hepatocellular carcinoma (HCC) is one of the most lethal malignancies, whose initiation and development are driven by alterations in driver genes. In this study, we identified four driver genes (TP53, PTEN, CTNNB1, and KRAS) that exhibit a high frequency of somatic mutations or copy number variations (CNVs) in patients with HCC. Four different spontaneous HCC mouse models were constructed to screen for changes in various kinase signaling pathways. The sgTrp53+sgPten tumor upregulated mTOR and noncanonical NF-κB signaling, which was shown to be strongly inhibited by rapamycin (an mTOR inhibitor) in vitro and in vivo. JAK-STAT signaling was activated in the Ctnnb1 mut +sgPten tumor, the proliferation of which was strongly inhibited by napabucasin (a STAT3 inhibitor). MTOR, cytoskeleton, and AMPK signaling were upregulated while rapamycin and ezrin inhibitors exerted potent anti-proliferative effects in the sgPten+Kras G12D tumor. JAK-STAT, MAPK, and cytoskeleton signaling were activated in the sgTrp53+Kras G12D tumor and the combination of sorafenib and napabucasin led to the complete inhibition of tumor growth in vivo. In patients with HCC, who had the same molecular classification as our mouse models, the downstream signaling pathway landscapes associated with genomic alterations were identical. Our research provides novel targeted therapeutic options for the clinical treatment of HCC, based on the presence of specific genetic alterations within the tumor.