期刊
GASTROENTEROLOGY
卷 135, 期 6, 页码 1972-1983出版社
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2008.08.008
关键词
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资金
- Fundacion Pedro Barrie de la Maza
- Asociacion Espahola para el Estudio del Higado
- National Cancer Center
- Instituto de Salud Carlos III [FIS-CM04/00044]
- Italian Association for Cancer Research
- Italian National Ministry of Health
- Instituto Carlos III [ISCIII/FIS PI 05-0150]
- Institucio Catalana de Recerca I Estudis Avanqats
- U.S. National Institute of Diabetes and Digestive and Kidney Diseases [1R01DK076986-01.]
- Samuel Waxman Cancer Research Foundation
- Spanish National Health Institute [SAF-2007-61898]
- National Institutes of Health [1R01DK37340-23]
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK037340, R01DK076986] Funding Source: NIH RePORTER
- ICREA Funding Source: Custom
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.
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