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KEGG's kidney cancer map shows how losing VHL lets the oxygen sensor HIF pile up and order new blood vessels (VEGF, PDGF), while MET and PI3K drive growth in other subtypes. Anti-VEGF drugs, HIF-2a inhibitors and immunotherapy all act on this circuit.
The KEGG renal cell carcinoma map (hsa05211) organises RCC by subtype and driver gene. In clear cell RCC, the majority, the VHL tumour suppressor is lost. VHL is the substrate-recognition part of an E3 ubiquitin ligase (with elongin B and C, CUL2 and RBX1) that degrades the alpha subunits of hypoxia-inducible factor once prolyl hydroxylases (EGLN1 to EGLN3) have marked them in the presence of oxygen. Without VHL, HIF-1a and especially HIF-2a (EPAS1) accumulate, pair with ARNT and switch on VEGFA, PDGFB, TGFA, GLUT1 (SLC2A1) and other hypoxia genes, producing a highly vascular tumour even in normal oxygen. In hereditary and sporadic papillary RCC, activating MET mutations (with its ligand HGF) drive GAB1, RAS to ERK, PI3K to AKT and RAC/PAK signalling for motility and invasion. Loss of fumarate hydratase (FH) accumulates fumarate, which inhibits the prolyl hydroxylases and again stabilises HIF; folliculin (FLCN) loss underlies Birt-Hogg-Dube syndrome; and PRCC-TFE3 fusions define translocation RCC. Hsieh et al., Nat Rev Dis Primers, 2017 (doi:10.1038/nrdp.2017.9) review this genetics, adding the chromatin genes PBRM1, SETD2, BAP1 and KDM5C that are co-deleted or mutated on chromosome 3p alongside VHL.
What drugs do about it: VEGF receptor tyrosine kinase inhibitors (sunitinib, pazopanib, axitinib, cabozantinib which also hits MET, and lenvatinib) and the VEGF antibody bevacizumab starve the HIF-driven vasculature; belzutifan blocks HIF-2a directly and is approved for VHL disease and previously treated clear cell RCC; mTOR inhibitors everolimus and temsirolimus act on the PI3K axis; and PD-1 antibodies (nivolumab, pembrolizumab) combined with a VEGFR TKI or with ipilimumab are the standard first-line regimens.
VHL is the bin lorry that removes HIF every day. When it stops coming, HIF piles up and sends out non-stop orders for new blood vessels. Anti-VEGF drugs intercept the orders; belzutifan gags HIF-2a so the orders are never written.
Shares HIF-1α (HIF1A), Axitinib, VHL / HIF oxygen sensing, Pazopanib.
Shares mTOR, VHL / HIF oxygen sensing, HIF-2α, Belzutifan.
Shares mTOR, VEGF angiogenesis, Cabozantinib, MET.
Shares Axitinib, Cabozantinib, Lenvatinib, Ipilimumab.
Shares HGF, Savolitinib, VEGF angiogenesis, PI3K / AKT / mTOR.
Shares Temsirolimus, mTOR, Everolimus, Renal cell carcinoma.
Shares MET, PI3K / AKT / mTOR, Receptor tyrosine kinase activation, PD-1 / PD-L1 immune checkpoint & T-cell activation.
Shares HIF-1α (HIF1A), VHL, Axitinib, HIF-2α.