Seventy-five percent of lung adenocarcinomas with epidermal growth factor 
receptor (EGFR) mutations respond to treatment with the tyrosine kinase 
inhibitors (TKIs) gefitinib and erlotinib; however, drug-resistant tumors 
eventually emerge. In 60% of cases, resistant tumors carry a secondary mutation 
in EGFR (T790M), amplification of MET, or both. Here, we describe the 
establishment of erlotinib resistance in lung tumors, which were induced by 
mutant EGFR, in transgenic mice after multiple cycles of drug treatment; we 
detect the T790M mutation in five out of 24 tumors or Met amplification in one 
out of 11 tumors in these mice. This preclinical mouse model, therefore, 
recapitulates the molecular changes responsible for resistance to TKIs in human 
tumors and holds promise for the discovery of additional mechanisms of drug 
resistance in lung cancer.