Synergistic Antitumor Activity and Neuroprotective Effects of FGF1/FGFR Inhibition with Oxaliplatin Chemotherapy.

[INTRODUCTION] Oxaliplatin is a first-line chemotherapeutic agent for cancer treatment, but the monotherapy effect is limited.Oxaliplatin-induced peripheral neurotoxicity (OIPN) is a dose-limiting clinical problem, leading to decreased quality of life or even treatment discontinuation. Fibroblast growth factor 1 (FGF1) was initially identified in the pituitary gland and the brain as a substance that promotes mitosis in fibroblasts, however, dysregulated FGF1 expression is associated with human pathologies, particularly cancer.

[OBJECTIVES] Our study aimed to propose a combination therapeutic strategy to overcome the suboptimal efficacy and neurotoxic side effects of oxaliplatin monotherapy.

[METHODS] We first performed transcriptomic sequencing and then constructed FGF1 knockdown and overexpression cell lines to elucidate FGF1's role in tumor progression and its impact on oxaliplatin's chemotherapeutic effect. Furthermore, behavioral experiments in tumor-bearing mice and transmission electron microscopy (TEM) of sciatic nerves were used to evaluate the role of FGF1 in OIPN. Finally, mechanistic studies using Western blotting (WB) and immunohistochemistry (IHC) elucidated the molecular pathways regulated by FGF1.

[RESULTS] Our study found that FGF1 expression was increased in hepatocellular carcinoma and lung cancer cells and the dorsal root ganglia (DRG) of tumor-bearing mice after oxaliplatin treatment. FGF1 overexpression promoted tumor growth and exacerbated neuronal damage. Conversely, knockdown of FGF1 not only enhanced the anti-tumor efficacy of oxaliplatin but also markedly reduced oxaliplatin-induced neurotoxicity. Mechanistic investigations revealed that FGF1 promotes cancer progression and exacerbates neurological damage by acting on the FGFR pathway. Strikingly, the combination of oxaliplatin and FGFR inhibitors inhibited tumor growth to a greater extent and provided obvious relief from the neurotoxicity produced by oxaliplatin.

[CONCLUSION] FGF1 promotes tumor progression and impairs oxaliplatin's therapeutic efficacy by activating the FGFR signaling pathway, while also inducing neuropathic injury. Notably, combining oxaliplatin with FGFR inhibitors enhances antitumor efficacy and alleviates oxaliplatin-induced peripheral neuropathy (OIPN) symptoms.