EGFR inhibitor suppresses tumor growth by blocking lipid uptake and cholesterol synthesis in non-small cell lung cancer

Accelerated cholesterol and lipid metabolism are hallmarks of non-small cell lung cancer (NSCLC). Recently, epidermal growth factor receptor (EGFR) signaling has been shown to regulate de novo cholesterol synthesis and low-density lipoprotein receptor (LDLR) expression through SREBP-1-dependent pathways. This suggests that targeting EGFR signaling in cholesterol metabolism might provide a new therapeutic strategy for NSCLC. In this study, we demonstrated that AX-0085, a small-molecule drug, significantly inhibits EGFR kinase activity and subsequently suppresses cholesterol and lipid metabolism in NSCLC. Transcriptomic analysis showed that cholesterol and lipid metabolism-related transcripts were significantly downregulated in AX-0085-treated NSCLC cells compared to the mock control. In addition, AX-0085 downregulates EGF signaling-dependent SREBP1-mediated cholesterol biosynthesis-related enzymes and LDLR in NSCLC. Moreover, AX-0085 dramatically reduced proliferation, colony-forming ability, and migration in NSCLC cells by blocking EGFR signaling. Furthermore, treatment with AX-0085 decreased both tumor size and volume in the LLC-xenograft model. These results demonstrate that AX-0085 effectively suppresses cholesterol metabolism in NSCLC cells by inhibiting EGF-mediated SREBP1 signaling, suggesting a potential therapeutic strategy targeting cholesterol metabolism in NSCLC.