Lung cancers harboring mutations in the epidermal growth factor receptor (EGFR) 
respond to EGFR tyrosine kinase inhibitors, but drug resistance invariably 
emerges. To elucidate mechanisms of acquired drug resistance, we performed 
systematic genetic and histological analyses of tumor biopsies from 37 patients 
with drug-resistant non-small cell lung cancers (NSCLCs) carrying EGFR 
mutations. All drug-resistant tumors retained their original activating EGFR 
mutations, and some acquired known mechanisms of resistance including the EGFR 
T790M mutation or MET gene amplification. Some resistant cancers showed 
unexpected genetic changes including EGFR amplification and mutations in the 
PIK3CA gene, whereas others underwent a pronounced epithelial-to-mesenchymal 
transition. Surprisingly, five resistant tumors (14%) transformed from NSCLC 
into small cell lung cancer (SCLC) and were sensitive to standard SCLC 
treatments. In three patients, serial biopsies revealed that genetic mechanisms 
of resistance were lost in the absence of the continued selective pressure of 
EGFR inhibitor treatment, and such cancers were sensitive to a second round of 
treatment with EGFR inhibitors. Collectively, these results deepen our 
understanding of resistance to EGFR inhibitors and underscore the importance of 
repeatedly assessing cancers throughout the course of the disease.