Structural and mechanistic underpinnings of the differential drug sensitivity of EGFR mutations in non-small cell lung cancer

Biochim Biophys Acta. 2010 Mar;1804(3):559-66. doi: 10.1016/j.bbapap.2009.12.010. Epub 2009 Dec 22.


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.

Publication types

  • Review

MeSH terms

  • Animals
  • Catalytic Domain / drug effects
  • Catalytic Domain / genetics
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics*
  • Enzyme Activation / drug effects
  • Enzyme Activation / genetics
  • ErbB Receptors* / chemistry
  • ErbB Receptors* / genetics
  • ErbB Receptors* / metabolism
  • Erlotinib Hydrochloride
  • Gefitinib
  • Humans
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / enzymology
  • Lung Neoplasms* / genetics
  • Mutation*
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / therapeutic use
  • Protein Structure, Tertiary / genetics
  • Quinazolines / chemistry*
  • Quinazolines / therapeutic use
  • Small Cell Lung Carcinoma* / drug therapy
  • Small Cell Lung Carcinoma* / enzymology
  • Small Cell Lung Carcinoma* / genetics
  • Structure-Activity Relationship


  • Protein Kinase Inhibitors
  • Quinazolines
  • Erlotinib Hydrochloride
  • EGFR protein, human
  • ErbB Receptors
  • Gefitinib