Biological pathways targeted for therapy in renal cell carcinoma based on a knowledge of the underlying genetic changes and downstream biological consequences. Loss of function of the VHL tumour suppressor gene leads to stabilisation of hypoxia-inducible factor alpha (HIFα). Activated HIF translocates into the nucleus and leads to the transcription of a large number of hypoxia-inducible genes including vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF). Mammalian target of rapamycin (mTOR) is a kinase within the PI3K/Akt pathway that can promote cell growth and survival pathways as well as causing accumulation of HIF. Bevacizumab is a monoclonal antibody to VEGF whilst sunitinib, sorafenib, axitinib and pazopanib are VEGF receptor tyrosine kinase inhibitors. These agents are thought to primarily function as antiangiogenic agents, inhibiting ligand binding or downstream receptor signalling of VEGF and PDGF on endothelial cells. Temsirolimus and everolimus inhibit the kinase activity of the mTOR complex 1 (mTORC1). Reproduced with permission from Elsevier©. From . HIF: hypoxia-inducible factor; mTOR: mammalian target of rapamycin; mTORC1: mTOR complex 1; PDGF: platelet derived growth factor; PTEN: phosphatase and tensin homolog; VEGF: vascular endothelial growth factor; VEGFR: vascular endothelial growth factor receptor.
Vasudev et al. BMC Medicine 2012 10:112 doi:10.1186/1741-7015-10-112