Adiponectin Receptor 1-vascular endothelial growth factor axis mediates resistance to epidermal growth factor receptor-targeted therapy in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is highly prevalent in Southeast Asia and southern China, with most patients diagnosed at advanced stages. Although epidermal growth factor receptor (EGFR)-targeted therapies have shown clinical promise, their long-term efficacy is limited. This study explores the regulatory role of AdipoR1 in EGFR-targeted therapy response and evaluates adiponectin as a potential strategy to overcome treatment resistance. NPC cell lines (5-8F and CNE1) were treated with nimotuzumab for short (24 h) and long (72 h) durations. mRNA and protein expression of vascular endothelial growth factor (VEGF), AdipoR1/R2, and other pathway components were assessed using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blotting. Adiponectin was applied to explore its regulatory role in VEGF expression and EGFR signaling. Prolonged treatment of NPC cells with nimotuzumab inhibited EGFR downstream signaling [protein kinase B, mammalian target of rapamycin (mTOR), extracellular signal-regulated kinase], reduced cell invasion and migration initially, but invasive capacity gradually recovered over time. VEGF expression remained unchanged at 24 h but significantly increased after 72 h, promoting angiogenesis in cocultured HUVECs. Long-term nimotuzumab exposure downregulated AdipoR1 expression, while adiponectin restored AdipoR1 and VEGF levels with decreased mTOR expression, not EGFR, indicating that the mTOR pathway may mediate this regulation. In addition, nimotuzumab elevated the expression of lipid metabolism-related genes, FABP4 and CD36, which was mitigated by A-PN cotreatment. Prolonged EGFR-targeted therapy in NPC upregulates VEGF via AdipoR1 downregulation, reducing treatment efficacy. Adiponectin restores AdipoR1, suppresses VEGF, and reverses this effect, possibly through mTOR inhibition, suggesting a potential strategy to improve long-term therapeutic outcomes.