Journal
BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS
Volume 1804, Issue 3, Pages 559-566Publisher
ELSEVIER
DOI: 10.1016/j.bbapap.2009.12.010
Keywords
Tyrosine kinase; Epidermal growth factor receptor; X-ray crystallography; Gefitinib; Lung cancer; Drug resistance
Categories
Funding
- NCI NIH HHS [R01 CA080942-09, R01 CA080942, R01 CA116020-02, R01 CA080942-08, R01 CA080942-07, R01 CA116020-01A1, R01 CA116020-03, R01 CA116020, R01 CA080942-10, R01 CA080942-06A1, R01 CA116020-04, R01 CA116020-05] Funding Source: Medline
- NHLBI NIH HHS [P01 HL048675-130012, P01 HL048675-160012, P01 HL048675, P01 HL048675-150012, P01 HL048675-170012, P01 HL048675-140012] Funding Source: Medline
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EGFR and other ErbB-family tyrosine kinases are overexpressed in many human tumors, and their aberrant expression and mutational activation is associated with the development, progression and aggressiveness of a number of malignancies. Thus the EGFR kinase has long been recognized as a potential drug target in oncology, and small-molecule inhibitors have been under development for more than two decades. As a result of their effectiveness in treating non-small cell lung cancers (NSCLCs) driven by somatic mutations in the EGFR kinase, gefitinib and erlotinib were the first EGFR tyrosine kinase inhibitors (TKIs) approved for clinical use. Ironically, these drugs found their target against mutant forms of the EGFR kinase, which have altered enzyme active sites, and not against the wild type (WT) kinase against which their potency and selectivity was carefully honed. Here we review recent structural and enzymological studies that explore the exquisite sensitivity of a subset of these lung cancer mutants to gefitinib and erlotinib. We discuss available structural evidence for the mechanisms of activation of the EGFR kinase by these mutants, and compare it to physiologic activation of the kinase by ligand-induced dimerization. Finally, we consider the mechanisms by which the secondary T790M gatekeeper mutation confers resistance to gefitinib and erlotinib. (C) 2009 Elsevier B.V. All rights reserved.
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