BACKGROUND: Lung adenocarcinomas from patients who respond to the tyrosine 
kinase inhibitors gefitinib (Iressa) or erlotinib (Tarceva) usually harbor 
somatic gain-of-function mutations in exons encoding the kinase domain of the 
epidermal growth factor receptor (EGFR). Despite initial responses, patients 
eventually progress by unknown mechanisms of "acquired" resistance.
METHODS AND FINDINGS: We show that in two of five patients with acquired 
resistance to gefitinib or erlotinib, progressing tumors contain, in addition to 
a primary drug-sensitive mutation in EGFR, a secondary mutation in exon 20, 
which leads to substitution of methionine for threonine at position 790 (T790M) 
in the kinase domain. Tumor cells from a sixth patient with a drug-sensitive 
EGFR mutation whose tumor progressed on adjuvant gefitinib after complete 
resection also contained the T790M mutation. This mutation was not detected in 
untreated tumor samples. Moreover, no tumors with acquired resistance had KRAS 
mutations, which have been associated with primary resistance to these drugs. 
Biochemical analyses of transfected cells and growth inhibition studies with 
lung cancer cell lines demonstrate that the T790M mutation confers resistance to 
EGFR mutants usually sensitive to either gefitinib or erlotinib. Interestingly, 
a mutation analogous to T790M has been observed in other kinases with acquired 
resistance to another kinase inhibitor, imatinib (Gleevec).
CONCLUSION: In patients with tumors bearing gefitinib- or erlotinib-sensitive 
EGFR mutations, resistant subclones containing an additional EGFR mutation 
emerge in the presence of drug. This observation should help guide the search 
for more effective therapy against a specific subset of lung cancers.