Biological pathways and the resulting therapeutic targets in renal cell carcinoma

In conditions of normoxia and normal VHL gene function, von Hippel-Landau protein is the substrate recognition component of an E3 ubiquitin ligase complex that targets hypoxia-inducible factor (HIF) for proteolysis. In cellular hypoxia or with an inactivated VHL gene, the VHL proteinHIF interaction is disrupted, leading to stabilisation and accumulation of HIF transcription factors. HIF accumulation can also result from activation of the mammalian target of rapamycin (mTOR) through cellular stimuli and the phosphoinositide 3-kinase (PI3K)/Akt (protein kinase) pathway. mTOR phosphorylates and activates p70S6 kinase (p70S6K) leading to enhanced translation of certain proteins, including HIF. Activated mTOR also phosphorylates 4E binding protein-1 (4E-BP1), promoting dissociation of this complex and allowing eukaryotic initiation factor-4 subunit E (eIF-4E) to stimulate an increase in the translation of mRNAs that encode cell-cycle regulators such as c-myc and cyclin D1. Activated HIF translocates into the nucleus and leads to transcription of a large range of hypoxia-inducible genes, including vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). These ligands bind to their cognate receptors present on the surface of endothelial cells, leading to cell migration, proliferation, and permeability. Temsirolimus binds to FK506-binding protein (FKBP), and the resultant proteindrug complex inhibits the kinase activity of the mTOR complex 1 (mTORC1). Bevacizumab is a VEGF ligand-binding antibody. Sunitinib and sorafenib are small molecule inhibitors of the VEGF receptor (VEGFR) and PDGF receptor (PDGRF) tyrosine kinases.