A study from Sakari Vanharanta’s group (MRC Cancer Unit) elucidates previously uncharacterised molecular mechanisms underlying clear cell Renal Cell Carcinoma (ccRCC) pathogenesis.
 
ccRCC is the most common subtype of kidney cancer and is characterised by biallelic inactivation of von Hippel Lindau tumour suppressor gene (VHL), 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 five-year survival at less than 10%.
 
The results, published in Nature Communications, 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. Thus, these results reveal a molecular link between two approved kidney cancer therapeutic targets, PDGFR and mTORC1.
 
These new findings highlight the links between super enhancer-driven transcriptional networks and the activity of essential metabolic pathways. The detailed understanding of such links could pave the way for novel therapeutic intervention strategies.