Reduction in gefitinib resistance mediated by Yi-Fei San-Jie pill in non-small cell lung cancer through regulation of tyrosine metabolism, cell cycle, and the MET/EGFR signaling pathway.

The Chinese herbal prescription Yi-Fei San-Jie pill (YFSJ) has been used for adjuvant treatment in patients with lung cancer for a long time. Reports have indicated that the combination of gefitinib (Gef) with YFSJ inhibits the proliferation of EGFR-TKI-resistant cell lines by enhancing cellular apoptosis and autophagy in non-small cell lung cancer (NSCLC). However, the molecular mechanisms underlying the effect of YFSJ on EGFR-TKI resistance and related metabolic pathways remain to be explored. In our report, ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), metabolomics, network pharmacology, bioinformatics, and biological analysis methods were used to investigate the mechanism. The UPLC-MS/MS data identified 42 active compounds of YFSJ extracts. YFSJ extracts can enhance the antitumor efficacy of Gef without hepatic and renal toxicity in vivo. The analysis of the metabolomics pathway enrichment revealed that YFSJ mainly affected the tyrosine metabolism pathway in rat models. Moreover, YFSJ has been shown to reverse Gef resistance and improve the effects of Gef on the cellular viability, migration capacity, and cell cycle arrest of NSCLC cell lines with EGFR mutations. The results of network pharmacology and molecular docking analyses revealed that tyrosine metabolism-related active compounds of YFSJ affect EGFR-TKIs resistance in NSCLC by targeting cell cycle and the MET/EGFR signaling pathway; these findings were validated by western blotting and immunohistochemistry. YFSJ inhibits NSCLC by inducing cell cycle arrest in the G1/S phase to suppress tumor growth, cell viability, and cell migration through synergistic effects with Gef via the tyrosine metabolic pathway and the EGFR/MET signaling pathway. To summarize, the findings of the current study indicate that YFSJ is a prospective complementary treatment for Gef-resistant NSCLC. [Display omitted] • The mechanism of Yi-Fei San-Jie pill in reducing epidermal growth factor receptor tyrosine kinase inhibitors resistance could be via its tyrosine metabolism-related antitumor compounds that regulate the MET/EGFR/CDK2 pathway involved in tyrosine metabolism, tumor growth inhibition, and cell cycle arrest in non–small cell lung cancer. • Various cyclins and cyclin-dependent kinases, including CDK2 and CDK4, regulate the cell cycle and the sensitivity to epidermal growth factor receptor tyrosine kinase inhibitors in cancer cells. • EGFR signaling is involved in cell cycle regulation and cell proliferation via the activation of cyclin-dependent kinases, such as CDK2 and CDK4. • Resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non–small cell lung cancer is associated with upregulation of MET signaling. [ABSTRACT FROM AUTHOR]