Mechanistic insights into the activation of oncogenic forms of EGF receptor

The EGFR receptor tyrosine kinase is frequently mutated in lung cancer, but the mechanism by which mutations activate kinase activity are not clear. Using purified, nearly full-length EGFR, it is now seen that mutations drive activation and resistance to inhibitors through the formation of the asymmetric kinase domain dimer. Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that is commonly activated by mutation in non–small cell lung cancer. The mechanism of this oncogenic activation is not completely understood, but in contrast to that of the wild-type EGFR, it is proposed to be independent of kinase domain dimerization. Mechanistic studies on EGFR have mainly relied on cell-based assays or isolated kinase domain measurements. Here we show, using purified, near full-length human EGFR proteins (tEGFRs), that two oncogenic mutants are fully active independently of EGF and highly resistant to the therapeutic and endogenous inhibitors cetuximab, lapatinib and MIG6. Based on the pattern of inhibition and the effects of additional asymmetric kinase dimer interface mutations, we propose that these oncogenic EGFR mutants drive and strongly depend on the formation of the asymmetric kinase dimer for activation, which has implications for drug design and cancer treatment strategies.