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

Abstract

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.

Exploring the JAK/STAT Signaling Pathway in Hepatocellular Carcinoma: Unraveling Signaling Complexity and Therapeutic Implications

“…Importantly, the treatment resulted in the downregulation of pSTAT3 and stemness markers such as Nanog, CD133, Klf4, Oct4, and Sox2 [134]. In another study, tumors induced by activated beta-catenin and mTOR signaling were highly susceptible to napabucasin, which strongly inhibited the proliferation of the tumor cells [135].…”

“…In vitro and in vivo animal studies have demonstrated that napabucasin has a strong anti-tumor effect on HCC, as the STAT3 inhibitor suppresses cell viability and proliferation, as well as downregulates expression of stemness genes [134,135]. Based on promising preclinical results, a clinical trial evaluated the co-administration of sorafenib and napabucasin for potential benefits in advanced HCC patients over sorafenib treatment alone.…”

Exploring the JAK/STAT Signaling Pathway in Hepatocellular Carcinoma: Unraveling Signaling Complexity and Therapeutic Implications

“…Importantly, the treatment resulted in the downregulation of pSTAT3 and stemness markers such as Nanog, CD133, Klf4, Oct4, and Sox2 [ 158 ]. In another study, tumors induced by activated beta-catenin and mTOR signaling were highly susceptible to napabucasin, which strongly inhibited the proliferation of the tumor cells [ 159 ].…”

“…In vitro and in vivo animal studies have demonstrated that napabucasin has a strong antitumor effect on HCC, as the STAT3 inhibitor suppresses cell viability and proliferation, as well as downregulating expression of stemness genes [ 158 , 159 ]. Based on promising preclinical results, a clinical trial evaluated the co-administration of sorafenib and napabucasin for potential benefits in advanced HCC patients over sorafenib treatment alone.…”