FGFRL1 Modulates Notch Signaling and Glucose-Glycogen Homeostasis to Suppress Chemoresistance in Esophageal Carcinoma

Chemoresistance remains a significant barrier to the treatment of esophageal cancer (EC), regulated by metabolic and signaling adaptations. Fibroblast Growth Factor Receptor-Like 1 (FGFRL1) is a key regulator of cancer progression; however, its involvement in driving chemoresistance remains poorly understood. This study investigates the functional significance of FGFRL1 in chemo-resistant EC cells and its association with response to chemotherapy. FGFRL1 expression was analyzed in cisplatin-resistant EC cells using real-time PCR and Western blotting. FGFRL1 protein levels were examined in clinical specimens from EC patients post-neoadjuvant chemotherapy (NACT) to evaluate their correlation with treatment response using immunohistochemistry. Significantly decreased expression of FGFRL1 was observed in cisplatin-resistant EC cells (p < 0.05). Interestingly, overexpression of FGFRL1 suppressed proliferation, migration, and clonogenic potential (p < 0.05), while activating Notch signaling via JAG1, DLL1, DLL4, NOTCH1, NOTCH2, and HES1 (p < 0.05) in cisplatin-resistant EC cells. FGFRL1 overexpression also shifted glucose metabolism toward glycogen synthesis, involving regulators GFPT2, AQP3, and GALT5 (p < 0.05). In patient specimens, FGFRL1 upregulation was significantly associated with chemotherapy response, observed in 80% of complete responders versus 36.4% of non-responders (p = 0.000, OR = 8.61). We report for the first time that FGFRL1 regulates metabolic and signaling pathways in chemo-resistant EC, suggesting its potential as a drug target to counter resistance.