Targeting the FGF19/FGFR4 positive feedback loop to disrupt ERK-mediated tumor progression in head and neck cancer

BACKGROUND: Head and neck cancer (HNC) is a biologically heterogeneous malignancy with limited actionable therapeutic targets. The fibroblast growth factor receptor (FGFR) family comprises receptor tyrosine kinases implicated in tumor progression; however, their specific roles in HNC remain incompletely defined. METHODS: Genomic alterations, transcriptomic profiles, and clinical relevance of FGFR1–FGFR4 were assessed in the TCGA/HNC cohort and in an independent validation set. Gain- and loss-of-function assays were performed to examine FGFR4 in cell motility, clonogenicity, and chemoresistance. Bioinformatic analyses and pharmacological perturbations were used to delineate FGFR4 regulatory mechanisms. RESULTS: Among FGFR family members, FGFR4 was consistently overexpressed in HNC tissues and associated with poor prognosis. Functionally, FGFR4 promoted migration, invasion, and clonogenicity without affecting proliferation. Mechanistically, FGFR4 induced ERK activation, which upregulated RUNX3 and subsequently increased MMP2 expression. Pharmacological ERK inhibition suppressed RUNX3-MMP2 axis and attenuated migration and invasion in FGFR4-overexpressing cells. FGFR4 overexpression also conferred resistance to cisplatin, 5-fluorouracil, and docetaxel. Trametinib partially restored chemosensitivity in vitro and markedly enhanced cisplatin efficacy in vivo. Additionally, ERK activation increased both FGFR4 and FGF19 expressions, whereas ERK inhibition suppressed FGF19 and FGFR4 upregulation observed in HNC cells. Moreover, exogenous FGF19 further induced FGFR4 expression and ERK activation, consistent with a self-reinforcing FGF19–FGFR4–ERK feedback loop. CONCLUSION: FGFR4 functions as an oncogenic driver in HNC, promoting tumor progression through the ERK–RUNX3–MMP2 axis and mediating chemoresistance via FGFR4–ERK signaling. The ERK-dependent induction of FGF19 and FGFR4 establishes a positive feedback circuit that sustains oncogenic activation. Targeting the FGF19/FGFR4 axis, particularly when combined with MEK/ERK inhibitors, represents a promising strategy to overcome resistance in HNC.