Epigallocatechin gallate circumvents drug‐induced resistance in non‐small‐cell lung cancer by modulating glucose metabolism and AMPK/AKT/MAPK axis

Upon prolonged use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in non-small-cell lung cancer (NSCLC), acquired drug resistance inevitably occurs. This study investigates the combined use of EGFR-TKIs (gefitinib or osimertinib) with epigallocatechin gallate (EGCG) to overcome acquired drug resistance in NSCLC models. The in vitro antiproliferative effects of EGFR-TKIs and EGCG combination in EGFR-mutant parental and resistant cell lines were evaluated. The in vivo efficacy of the combination was assessed in xenograft mouse models derived from EGFR-TKI-resistant NSCLC cells. We found that the combined use of EGFR-TKIs and EGCG significantly reversed the Warburg effect by suppressing glycolysis while boosting mitochondrial respiration, which was accompanied by increased cellular ROS and decreased lactate secretion. The combination effectively activated the AMPK pathway while inhibited both ERK/MAPK and AKT/mTOR pathways, leading to cell cycle arrest and apoptosis, particularly in drug-resistant NSCLC cells. The in vivo results obtained from mouse tumor xenograft model confirmed that EGCG effectively overcame osimertinib resistance. This study revealed that EGCG suppressed cancer bypass survival signaling and altered cancer metabolic profiles, which is a promising anticancer adjuvant of EGFR-TKIs to overcome acquired drug resistance in NSCLC.