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Interactions between driver genes shape the signaling pathway landscape and direct hepatocellular carcinoma therapy
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Interactions between driver genes shape the signaling pathway landscape and direct hepatocellular carcinoma therapy
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Journal Article
Interactions between driver genes shape the signaling pathway landscape and direct hepatocellular carcinoma therapy
2023
Overview
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 show 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 nuclear factor‐κB signaling, which was shown to be strongly inhibited by rapamycin (an mTOR inhibitor) in vitro and in vivo. The JAK‐signal transducer and activator of transcription (STAT) signaling was activated in Ctnnb1mut + sgPten tumor, the proliferation of which was strongly inhibited by napabucasin (a STAT3 inhibitor). Additionally, mTOR, cytoskeleton, and AMPK signaling were upregulated while rapamycin and ezrin inhibitors exerted potent antiproliferative effects in sgPten + KrasG12D tumor. We found that JAK‐STAT, MAPK, and cytoskeleton signaling were activated in sgTrp53 + KrasG12D 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. Hepatocellular carcinoma (HCC) is one of the most lethal and fastest growing malignancies worldwide. The authors aimed to investigate the differences between patients with HCC based on tumor molecular classification and provide targeted therapeutic options for them. The authors elucidated the cooperation between certain driver genes that leads to different transcriptomic and proteomic profiles, reflecting the intertumor complexity observed in HCC patients and screened out targeted inhibitors of sorafenib‐resistant tumors with different molecular classifications.
Publisher
John Wiley & Sons, Inc,John Wiley and Sons Inc
Subject
/ Animals
/ Carcinoma, Hepatocellular - drug therapy
/ Carcinoma, Hepatocellular - genetics
/ Carcinoma, Hepatocellular - metabolism
/ DNA Copy Number Variations - genetics
/ Ezrin
/ Genes
/ Genomes
/ Kinases
/ Liver Neoplasms - drug therapy
/ Liver Neoplasms - metabolism
/ Mice
/ Mutation
/ Original
/ Patients
/ Plasmids
/ Proto-Oncogene Proteins p21(ras) - genetics
/ Signal Transduction - genetics
/ Software
/ TOR Serine-Threonine Kinases - metabolism
/ Tumors
