Objective To observe the effects of erlotinib combined with choroquine on proliferation, apoptosis, and autophagy-associated protein expression of non-small-cell lung cancer( NSCLC) with wild-type epidermal growth factor receptor( EGFR). Methods Two NSCLC cell lines Spc-A1( wild-type K-RAS wild-type EGFR) and A549( K-RAS mutant wild-type EGFR) cultured in vitro were divided into four groups. The cells in the groups A, B, and C were added with erlotinib, choroquine, and erlotinib + choroquine( 0. 1 m L), respectively, and cells in the group D were added with the same amount of medium. MTT assay was performed to detect the cell proliferation after 72 hours of culture and the combination index of erlotinib and choroquine was calculated. Hoechst33258 staining was performed to observe apoptosis after 48 hours of culture. The expression of autophagy microtubule-associated protein light chain 3( LC3) was detected by Western blotting. Results The cell survival rates of groups A, B, C were lower than that of the group D( all P < 0. 05), and that of group C was lower than those of groups A and B( all P < 0. 05), the combination index of erlotinib and chloroquine was< 1. The apoptosis rates of Spc-A1 cells in the groups A, B, and C were 21. 1%, 12. 1%, and 48. 9%, respectively, which were higher than that( 8. 3%) of group D( all P < 0. 05), the apoptosis rates of A549 cells in the groups A, B, and C were 19. 3%, 13. 4%, and 51. 5%, which were higher than that( 10. 2%) of group D( all P < 0. 05), the apoptosis rate of group C was higher than those of groups A and B in both Spc-A1 and A549 cells( all P < 0. 05), meanwhile, the expression of autophagy-related protein LC3-Ⅰin the groups A, B, and C decreased with an increase in the LC3-Ⅱ expression( all P < 0. 05); compared with groups A and B, the expression of LC3-Ⅰin the group C reduced while the LC3-Ⅱ expression increased( all P < 0. 05). Conclusion The inhibition of erlotinib to NSCLC with wild-type EGFR can be sensitized by choroquine, which is not restricted by the K-RAS gene phenotype, and the mechanism may be that choroquine blocks the autophagy and promotes apoptosis. [ABSTRACT FROM AUTHOR]