ArticleJournal of hepatology2009
Ras pathway activation in hepatocellular carcinoma and anti-tumoral effect of combined sorafenib and rapamycin in vivo.
Article in Journal of hepatology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 106 papers.
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Who cites it
106 citing papers in PubMed, 220 citations in OpenAlex.
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- Corynoline enhances sorafenib sensitivity in hepatocellular carcinoma via NOS3-mediated ROS production.Chinese medicine · 2025Article
- BRAF inhibition increases TGFβ2 production and stimulates metastasis in mice with endogenous BRAFProceedings of the National Academy of Sciences of the United States of America · 2025Article
- Nelfinavir triggers ferroptosis by inducing ER stress mediated downregulation of GPX4/GSH system, upregulation of NRF2/HO-1 axis, and mitochondrial impairment in hepatocellular carcinoma cells.Cell death discovery · 2025Article
- Computational Network Pharmacology, Molecular Docking, and Molecular Dynamics to Decipher Natural Compounds ofPharmaceuticals (Basel, Switzerland) · 2025Article
- The impact of targeted therapies on molecular alterations identified by an institutional molecular tumor board: an approach based on ESCAT classification.ESMO real world data and digital oncology · 2024Article
- Overexpression of wild-type HRAS drives non-alcoholic steatohepatitis to hepatocellular carcinoma in mice.Zoological research · 2024Article
- KLHL7 promotes hepatocellular carcinoma progression and molecular therapy resistance by degrading RASA2.iScience · 2023Article
- LIN28 and histone H3K4 methylase induce TLR4 to generate tumor-initiating stem-like cells.iScience · 2023Article
- Molecular mechanisms of autophagy and implications in liver diseases.Liver research (Beijing, China) · 2023Review
- In Silico Analysis of MicroRNA Expression Data in Liver Cancer.Cancer informatics · 2023Article
- Protein phosphatases regulate the liver microenvironment in the development of hepatocellular carcinoma.Experimental & molecular medicine · 2022Review
- AK2 is an AMP-sensing negative regulator of BRAF in tumorigenesis.Cell death & disease · 2022Article
- RASSF1A independence and early galectin-1 upregulation in PIK3CA-induced hepatocarcinogenesis: new therapeutic venues.Molecular oncology · 2022Article
- Integrated systemic analysis of FAM72A to identify its clinical relevance, biological function, and relationship to drug sensitivity in hepatocellular carcinoma.Frontiers in oncology · 2022Article
- HCV and tumor-initiating stem-like cells.Frontiers in physiology · 2022Review
- Sorafenib treatment of metastatic melanoma with c-Kit aberration reduces tumor growth and promotes survival.Oncology letters · 2021Article
- Review
- Review
46 more citing papers are in PubMed but not listed here.
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Authors and funding
23 authors at 5 institutions in 2 countries.
Funding
Abstract
BACKGROUND/
aimsThe 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.
methodsGene 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.
resultsDifferent mechanisms accounted for Ras pathway activation in HCC. H-ras 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 RASSF1A and NORE1A 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.
conclusionsRas 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.
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