期刊
KIDNEY INTERNATIONAL
卷 76, 期 9, 页码 939-945出版社
ELSEVIER SCIENCE INC
DOI: 10.1038/ki.2009.296
关键词
clear-cell renal cell carcinoma; targeted therapy; tyrosine kinase inhibitor; von Hippel-Lindau
资金
- National Institutes of Health [K08 CA113452]
The basic biology underlying the development of clear-cell renal cell carcinoma (ccRCC) is critically dependent on the von Hippel-Lindau gene (VHL), whose protein product is important in the cell's normal response to hypoxia. Aberrations in VHL's function, either through mutation or promoter hypermethylation, lead to accumulation of the transcriptional regulatory molecule, hypoxia-inducible factor alpha (HIF alpha). HIF alpha can then dimerize with HIF beta and translocate to the nucleus, where it will transcriptionally upregulate a series of hypoxia-responsive genes, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and others. Binding of these ligands to their cognate receptors activates a series of kinase-dependent signaling pathways, including the RAF-MEK-ERK and phosphatidylinositol-3 kinase-AKT-mTOR pathways. Targeted agents developed and now approved for use in advanced ccRCC include humanized monoclonal antibodies against VEGF, small-molecule tyrosine kinase inhibitors, and inhibitors of mTOR. Understanding the biology of ccRCC is critical in understanding the current therapy for the disease and in developing novel therapeutics in the future. This review will provide an overview of the genetics of ccRCC, with an emphasis on how this has informed the development of the targeted therapeutics for this disease. Kidney International (2009) 76, 939-945; doi:10.1038/ki.2009.296; published online 5 August 2009
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