1. © 2005 Prentice Hall Inc. / A Pearson Education Company / Upper Saddle River, New Jersey 07458 Lung Cancer and Gefitinib  Lung cancer statistics in the United States  Estimated cases in 2004: ~174,000  Estimated deaths in 2004: ~160,000  Gefitinib (Iressa ™)  Developed by AstraZeneca  Used to treat Nonsmall Cell Lung Cancer (NSCLC)  Accounts for 85% of all lung cancers  90% of patients did not respond to drug  But, 10% responded incredibly well

2. © 2005 Prentice Hall Inc. / A Pearson Education Company / Upper Saddle River, New Jersey 07458 EGFR and Gefitinib Efficacy  Mutated protein kinases implicated in cancer  Gefitinib targets Epidermal Growth Factor Receptor (EGFR), a kinase  Gefitinib only effective in patients with mutated EGFR From Figure 3A in Paez, J. G. et al. (2004) “EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy” Science 304: 1497-1500.

3. © 2005 Prentice Hall Inc. / A Pearson Education Company / Upper Saddle River, New Jersey 07458 Mutations Accounting for Positive Drug Response  Mutations indicative of good gefitinib response  Segregated in areas implicated in autoregulation of kinases  P-loop  Activation loop From Figure 2 in Paez, J. G. et al. (2004) “EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy” Science 304: 1497-1500. EGFR kinase domain