Journal
JOURNAL OF HEPATOLOGY
Volume 51, Issue 4, Pages 725-733Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jhep.2009.03.028
Keywords
Liver cancer; HCV; Signaling pathway; Molecular therapies; Ras; mTOR
Categories
Funding
- NIH [1RO1 DK37340-23, 1R01DK076986-01]
- Associazione Italiana per la Ricerca sul Cancro Funding Source: Custom
- ICREA Funding Source: Custom
Ask authors/readers for more resources
Background/Aims: The success of sorafenib in the treatment of advanced hepatocellular carcinoma (HCC) has focused interest on the role of Ras signaling in this malignancy. We investigated the molecular alterations of the Ras pathway in HCC and the antineoplastic effects of sorafenib in combination with rapamycin, an inhibitor of mTOR pathway, in experimental models. Methods: Gene expression (qRT-PCR, oligonucleotide microarray), DNA copy number changes (SNP-array), methylation of tumor suppressor genes (methylation specific PCR) and protein activation (immunohistochemistry) were analysed in 351 samples. Anti-tumoral effects of combined therapy, targeting the Ras and mTOR pathways were evaluated in cell lines and HCC xenografts. Results: Different mechanisms accounted for Ras pathway activation in HCC. H-ran was up-regulated during different steps of hepatocarcinogenesis. B-raf was overexpressed in advanced tumors and its expression was associated with genomic amplification. Partial methylation of RASSFIA and NOREIA was detected in 89%, and 44%, of tumors respectively, and complete methylation was found in 11 and 4%, of HCCs. Activation of the pathway (PERK immunostaining) was identified in 10.3'% of HCC. Blockade of Ras and mTOR pathways with sorafenib and rapamycin reduced cell proliferation and induced apoptosis in cell lines. In vivo, the combination of both compounds enhanced tumor necrosis and ulceration when compared with sorafenib alone. Conclusions: Ras activation results from several molecular alterations, such as methylation of tumor suppressors and amplification of oncogenes (B-raf). Sorafenib blocks signaling and synergizes with rapamycin in vivo, preventing tumor progression. These data provide the rationale for testing this combination in clinical studies. (C) 2009 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available