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Structure and Clinical Relevance of the Epidermal Growth Factor Receptor in Human Cancer

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

From the Department of Pharmacology, Yale University School of Medicine, New Haven, CT; and the Division of Hematology/Oncology, Department of Medicine, Case Western Reserve University, Cleveland, OH

Corresponding author: Titus Boggon, Department of Pharmacology, Yale University School of Medicine, 333 Cedar St, SHM B-316A, New Haven, CT 06520-8066; e-mail: titus.boggon{at}yale.edu

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.

Supported by an American Society of Hematology Junior Faculty Award Scholarship (T.J.B.); National Institutes of Health (NIH)/ National Institute of Allergy and Infectious Diseases (NIAID) Grant No. 1R01AI075133 (T.J.B.); NIH/National Cancer Institute T32 training Grant No. 5T32CA009085 (E.T.P.); and a Young Clinical Scientist Award from the Flight Attendant Medical Research Institute (B.H.).

A.K. and E.T.P. contributed equally to this work.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.