Clear cell renal cell carcinoma (ccRCC), the most common subtype of kidney cancer, is characterised by biallelic inactivation of the VHL tumour suppressor gene, mTORC1 signalling pathway activation, and accumulation of cytoplasmic lipid. Inhibitors against receptor tyrosine kinases (e.g. VEGFR and PDGFR) and the mTORC1 complex are the current clinically approved therapies for ccRCC. Nevertheless, the overall objective response rates especially for advanced ccRCC remain low, with 5-year survival at less than 10%.
A recent study from Dr Sakari Vanharanta's group at the MRC Cancer Unit, published this month in Nature Communications, elucidates previously uncharacterised molecular mechanisms underlying ccRCC pathogenesis. The new results show that a cellular signalling network centred around Kruppel-like factor 6 (KLF6), a super enhancer-associated zinc finger transcription factor, promotes ccRCC growth by supporting lipid metabolism and mTORC1 activity. KLF6 activates mTORC1 through the expression of the secreted factor PDGFB, a ligand for the PDGFR receptor. These results reveal a molecular link between two approved kidney cancer therapeutic targets, PDGFR and mTORC1, and highlight the links between super enhancer-driven transcriptional networks and the activity of essential metabolic pathways. Detailed understanding of such links could pave the way for novel therapeutic intervention strategies.