Mechanistic insights into the activation of oncogenic forms of EGF receptor

Zhihong Wang, Patti A. Longo, Mary Katherine Tarrant, Kwangsoo Kim, Sarah Head, Daniel J. Leahy, Philip A. Cole

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1388-1393
Number of pages6
JournalNature structural & molecular biology
Volume18
Issue number12
DOIs
StatePublished - Dec 2011

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Epidermal Growth Factor Receptor
Phosphotransferases
Mutation
Drug Design
Receptor Protein-Tyrosine Kinases
Dimerization
Epidermal Growth Factor
Non-Small Cell Lung Carcinoma
Neoplasms
Proteins
Therapeutics

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

Cite this

Wang, Z., Longo, P. A., Tarrant, M. K., Kim, K., Head, S., Leahy, D. J., & Cole, P. A. (2011). Mechanistic insights into the activation of oncogenic forms of EGF receptor. Nature structural & molecular biology, 18(12), 1388-1393. https://doi.org/10.1038/nsmb.2168

Mechanistic insights into the activation of oncogenic forms of EGF receptor. / Wang, Zhihong; Longo, Patti A.; Tarrant, Mary Katherine; Kim, Kwangsoo; Head, Sarah; Leahy, Daniel J.; Cole, Philip A.

In: Nature structural & molecular biology, Vol. 18, No. 12, 12.2011, p. 1388-1393.

Research output: Contribution to journalArticle

Wang, Z, Longo, PA, Tarrant, MK, Kim, K, Head, S, Leahy, DJ & Cole, PA 2011, 'Mechanistic insights into the activation of oncogenic forms of EGF receptor', Nature structural & molecular biology, vol. 18, no. 12, pp. 1388-1393. https://doi.org/10.1038/nsmb.2168
Wang, Zhihong ; Longo, Patti A. ; Tarrant, Mary Katherine ; Kim, Kwangsoo ; Head, Sarah ; Leahy, Daniel J. ; Cole, Philip A. / Mechanistic insights into the activation of oncogenic forms of EGF receptor. In: Nature structural & molecular biology. 2011 ; Vol. 18, No. 12. pp. 1388-1393.
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