Pivotal role of mTOR signaling in hepatocellular carcinoma.

By A. Villanueva, Derek Y. Chiang, P. Newell, J. Peix, S. Thung, Clara Alsinet, V. Tovar, S. Roayaie, B. Mínguez, M. Solé and 16 more. Gastroenterology, 2008

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BACKGROUND & AIMS The advent of targeted therapies in hepatocellular carcinoma (HCC) has underscored the importance of pathway characterization to identify novel molecular targets for treatment. We evaluated mTOR signaling in human HCC, as well as the antitumoral effect of a dual-level blockade of the mTOR pathway. METHODS The mTOR pathway was assessed using integrated data from mutation analysis (direct sequencing), DNA copy number changes (SNP-array), messenger RNA levels (quantitative reverse-transcription polymerase chain reaction and gene expression microarray), and protein activation (immunostaining) in 351 human samples [HCC (n = 314) and nontumoral tissue (n = 37)]. Effects of dual blockade of mTOR signaling using a rapamycin analogue (everolimus) and an epidermal/vascular endothelial growth factor receptor inhibitor (AEE788) were evaluated in liver cancer cell lines and in a xenograft model. RESULTS Aberrant mTOR signaling (p-RPS6) was present in half of the cases, associated with insulin-like growth factor pathway activation, epidermal growth factor up-regulation, and PTEN dysregulation. PTEN and PI3KCA-B mutations were rare events. Chromosomal gains in RICTOR (25% of patients) and positive p-RPS6 staining correlated with recurrence. RICTOR-specific siRNA down-regulation reduced tumor cell viability in vitro. Blockage of mTOR signaling with everolimus in vitro and in a xenograft model decelerated tumor growth and increased survival. This effect was enhanced in vivo after epidermal growth factor blockade. CONCLUSIONS MTOR signaling has a critical role in the pathogenesis of HCC, with evidence for the role of RICTOR in hepato-oncogenesis. MTOR blockade with everolimus is effective in vivo. These findings establish a rationale for targeting the mTOR pathway in clinical trials in HCC.

Subfields: Hepatology, Molecular Biology, Surgery

View Paper: https://www.semanticscholar.org/paper/76fa11b4cdb19be3b003e8d1fb2dccc9708a54c5

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Citations in the corpus

EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. (2012, background): “It is activated in 40–50% of HCCs [312,313].”
miR-221 overexpression contributes to liver tumorigenesis (2009, background): “Thus, our data suggest that in liver tumors where PI3K-PTEN-AKT-mTORmutations remain conspicuously rare, the microtranscriptome may act as an important regulator of this pathway, which is considered to be crucial for hepatocarcinogenesis (29).”
EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. (2012, background): “It is activated in 40–50% of HCCs [312,313].”
Integrative Transcriptome Analysis Reveals Common Molecular Subclasses of Human Hepatocellular Carcinoma (2009, background): “The mechanism of AKTactivation in these tumors is not known but likely reflects upstream signaling of the phosphatidylinositol 3-kinase (PI3K) pathway (27).”
The interaction of hepatic lipid and glucose metabolism in liver diseases. (2012, background): “Several studies identified the insulin receptor downstream targets PI3-kinase/Akt and IRS to be activated in HCC when compared to surrounding healthy tissue, which mediates GSK3b phosphorylation and mTOR activation [124].”