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


CONCLUSIONS
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.
Kumar
Amit
A
Department of Pharmacology, Yale University School of Medicine, 333 Cedar St, SHM B-316A, New Haven, CT 06520-8066, USA.
Petri
Edward T
ET
Halmos
Balazs
B
Boggon
Titus J
TJ
D000970:Antineoplastic Agents / Q000494:pharmacology; D066246:ErbB Receptors / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D020836:Protein Structure, Quaternary; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D066246:ErbB Receptors