Eugenol as a game-changer: overcoming osimertinib resistance in non-small cell lung cancer by inhibiting glycolysis via the tripartite motif containing 59/extracellular signal-regulated kinase pathway.

Eugenol plays a significant role in various cancers and can influence the sensitivity of cancer cells to chemotherapy. This study aimed to investigate the mechanism by which eugenol regulates glycolysis through the tripartite motif containing 59 (TRIM59)/extracellular signal-regulated kinase (ERK) pathway in osimertinib-resistant non-small cell lung cancer (NSCLC). Drug-resistant lung cancer cell lines were established using osimertinib and treated with eugenol at different concentrations for 24†h. After treatment with eugenol, siTRIM59, TRIM59 overexpression, and the ERK inhibitor, either alone or in combination, the cell counting kit-8 was used to assess cell viability in drug-resistant cell lines. Flow cytometry, colony formation assay, and transwell assays were employed to evaluate the effects of eugenol on cell apoptosis, clonogenic ability, migration, and invasion, respectively. Relevant kits were used to measure the glycolytic activity of the cells. Eugenol inhibited the proliferation, invasion, and migration of drug-resistant cells, promoted apoptosis, and reduced glucose consumption, lactate release, and glycolytic activity in drug-resistant cells. TRIM59 expression was higher in drug-resistant cancer cells, while eugenol treatment inhibited the expression of TRIM59 and ERK phosphorylation. Silencing of TRIM59 enhanced the effect of eugenol on drug-resistant cell lines. Overexpression of TRIM59 reversed the effects of eugenol on drug-resistant cell lines, whereas ERK inhibition reversed the effects of TRIM59 and enhanced the therapeutic effects of eugenol on cancer cells. Moreover, eugenol inhibited the tumor growth, TRIM59 expression, and ERK phosphorylation in osimertinib-treated mice. Eugenol can effectively overcome osimertinib resistance in NSCLC by regulating glycolysis through the TRIM59/ERK signaling pathway. Eugenol could serve as a promising adjunctive therapy to improve chemotherapy efficacy and overcome drug resistance in NSCLC.