title: Mechanistic insights into the activation of oncogenic forms of EGF receptor.
abstract: 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.
authors.affiliation: Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Wang
authors.forename: Patti A
authors.initials: PA
authors.lastname: Longo
authors.forename: Mary Katherine
authors.initials: MK
authors.lastname: Tarrant
authors.forename: Kwangsoo
authors.initials: K
authors.lastname: Kim
authors.forename: Sarah
authors.initials: S
authors.lastname: Head
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Leahy
authors.forename: Philip A
authors.initials: PA
authors.lastname: Cole
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000068818:Cetuximab; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D000077341:Lapatinib; D008175:Lung Neoplasms / Q000235:genetics; D008958:Models, Molecular; D009154:Mutation; D011799:Quinazolines / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000737:chemistry
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D011799:Quinazolines; D025521:Tumor Suppressor Proteins; D000077341:Lapatinib; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068818:Cetuximab
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