Mechanistic insights into the activation of oncogenic forms of EGF receptor. Nat Struct Mol Biol 18: 1388–1393

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 incompletely understood but, in contrast to the WT EGFR, is proposed to be independent of kinase domain dimerization. Mechanistic studies on EGFR have largely relied on cell-based assays or isolated kinase domain measurements. Here we show using purified, near full-length EGFR proteins (tEGFRs) that two oncogenic mutants are fully active in the absence of EGF and highly resistant to the known 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. The epidermal growth factor receptor (EGFR) family comprises of four members in humans, EGFR (HER1), HER2/Neu, HER3, and HER41. These receptor tyrosine kinases (RTKs), play consequential roles in a variety of solid cancers and are the targets of many successfu