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

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Hepatocellular carcinoma (HCC) is a deadly cancer driven by genetic mutations.
• Identifying key driver genes and their associated signaling pathways is crucial for developing effective treatments.

Purpose of the Study:

• To identify driver genes in HCC and investigate their roles in signaling pathways.
• To explore targeted therapeutic strategies based on specific genetic alterations in HCC.

Main Methods:

• Identified four high-frequency driver genes (TP53, PTEN, CTNNB1, KRAS) in HCC patients.
• Developed four spontaneous HCC mouse models to study kinase signaling pathways.
• Utilized targeted inhibitors (rapamycin, napabucasin, sorafenib) and ezrin inhibitors in vitro and in vivo.

Main Results:

• sgTrp53 + sgPten tumors showed upregulated mTOR and NF-κB signaling, inhibited by rapamycin.
• Ctnnb1mut + sgPten tumors exhibited activated JAK-STAT signaling, inhibited by napabucasin.
• sgPten + KrasG12D tumors had upregulated mTOR, cytoskeleton, and AMPK signaling, responsive to rapamycin and ezrin inhibitors.
• sgTrp53 + KrasG12D tumors displayed activated JAK-STAT and MAPK signaling, with combined sorafenib and napabucasin achieving complete tumor inhibition.
• Identical downstream signaling pathway landscapes were observed in HCC patients and mouse models with similar genetic alterations.

Conclusions:

• Specific genetic alterations in HCC activate distinct signaling pathways.
• Targeted therapies, including rapamycin, napabucasin, and sorafenib, show significant efficacy against HCC driven by specific mutations.
• This research offers novel, genetically tailored therapeutic strategies for HCC treatment.