Background: The incidence and mortality of lung cancer are high, and treatment with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is the preferred first-line treatment for patients suffering from non-small cell lung cancer (NSCLC) with EGFR mutations. However, EGFR-TKI resistance leads to treatment failure. Yifei-Sanjie pill (YFSJ) is a novel type of Chinese patent medicine for lung cancer. The development of YFSJ has progressed for more than 30 years; however, little is known about the molecular mechanisms associated with the inhibition of drug resistance. Methods: In this study, flow cytometry and transcriptome sequencing were used in vitro to explore the anticancer effect of Yifei-Sanjie pill (YFSJ) on EGFR-TKI-resistant cell lines and to identify potential molecular mechanisms associated with the inhibition of drug resistance. Results: We found that in vitro, YFSJ and YFSJ combined with gefitinib significantly reduced the viability of H1975 and H1650 cells, which is dose-dependent at 24 and 48 h. PI3K, Akt and mTOR were downregulated, while after 24 and 48 h of treatment with YFSJ alone and in combination with gefitinib, LC3A and LC3B were up-regulated in both cell lines. Conclusion: YFSJ reduced the viability of EGFR-TKI-resistant cell lines, reducing resistance to gefitinib. This might be caused by a decrease in the PI3K/Akt/mTOR pathway and an increase in autophagy.
