01From signal to receptor
Growth factors like EGF bind receptor tyrosine kinases (RTKs) on the cell surface. Binding makes two receptors pair up (dimerize) and phosphorylate each other's tyrosines. Those phosphotyrosines become docking sites for adaptor proteins like GRB2, which recruit SOS.
SOS is a GEF — it swaps GDP for GTP on RAS, turning it on.
02The RAS switch
RAS is a small GTPase. RAS-GTP is active; RAS-GDP is inactive. RAS turns itself off by hydrolyzing GTP, helped by GAP proteins such as NF1. Active RAS starts a kinase cascade: RAF → MEK → ERK. ERK enters the nucleus and switches on growth genes including cyclin D and MYC.
Cancer-causing RAS mutations (codons 12, 13, 61) block GTP hydrolysis, so RAS is stuck on. KRAS is mutated in ~90% of pancreatic cancers. Losing the GAP NF1 has the same effect.
03Drugging the pathway
BRAF V600E occurs in about half of melanomas; vemurafenib and dabrafenib block it, often combined with MEK inhibitors to delay resistance. EGFR inhibitors (erlotinib, osimertinib) treat EGFR-mutant lung cancer. For decades RAS was 'undruggable' — until sotorasib, which locks KRAS G12C in its inactive state.