Structure and clinical relevance of the epidermal growth factor receptor in human cancer

Amit Kumar, Edward T. Petri, Balazs Halmos, Titus J. Boggon

Research output: Contribution to journalReview article

186 Citations (Scopus)

Abstract

Purpose: To review the recent advances in the atomic-level understanding of the epidermal growth factor receptor (EGFR) tyrosine kinase (TK). We aim to highlight the current and future importance of these studies for the understanding and treatment of malignancies where EGFR-TK is improperly activated. Methods: The analysis was conducted on published crystal structures deposited in the Protein Data Bank (www.pdb.org) using the program O. Results: In this review we emphasize how recent EGFR kinase domain crystal structures can explain the mechanisms of activation for L858R and other EGFR-TK mutations, and compare these distinct activating mechanisms with those recently described for the wild-type EGFR. We suggest an atomic-level mechanism for the poor efficacy of lapatinib against tumors with activating EGFR kinase domain point mutations compared with the efficacy of gefitinib and erlotinib, and demonstrate how structural insights help our understanding of acquired resistance to these agents. We also highlight how these new molecular-level structural data are expected to affect the development of EGFR-TK targeted small molecule kinase inhibitors. Conclusion: There are now more crystal structures published for the EGFR-TK domain than for any other TK. This wealth of crystallographic information is beginning to describe the mechanisms by which proper regulation of EGFR-TK is lost in disease. These crystal structures are beginning to show how small molecules inhibit EGFR-TK activity and will aid development of EGFR-TK mutant targeted therapies.

Original languageEnglish (US)
Pages (from-to)1742-1751
Number of pages10
JournalJournal of Clinical Oncology
Volume26
Issue number10
DOIs
StatePublished - 2008
Externally publishedYes

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Epidermal Growth Factor Receptor
Protein-Tyrosine Kinases
Neoplasms
Point Mutation
Phosphotransferases
Databases
Mutation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Structure and clinical relevance of the epidermal growth factor receptor in human cancer. / Kumar, Amit; Petri, Edward T.; Halmos, Balazs; Boggon, Titus J.

In: Journal of Clinical Oncology, Vol. 26, No. 10, 2008, p. 1742-1751.

Research output: Contribution to journalReview article

Kumar, Amit ; Petri, Edward T. ; Halmos, Balazs ; Boggon, Titus J. / Structure and clinical relevance of the epidermal growth factor receptor in human cancer. In: Journal of Clinical Oncology. 2008 ; Vol. 26, No. 10. pp. 1742-1751.
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