We established gefitinib resistant PC-9 cells which harbor EGFR exon 19 deletion....We observed heterozygous NRAS Q61K mutations in PC‐9/gef B4, PC‐9/gefE3, and PC‐9/gefE7 cells but not in the PC‐9/wt cell...Our in vivo studies showed that gefitinib inhibited growth of PC-9/wt xenografts but not PC-9/gef xenografts....In conclusion, persistent activation of the MAPK cascade possibly owing to NRAS mutation results in the acquired gefitinib resistance of lung adenocarcinoma harboring activation EGFR mutation...