Inhibition of the fgf/fgfr system induces apoptosis in lung cancer cells via c‐myc downregulation and oxidative stress

Abstract

Lung cancer represents an extremely diffused neoplastic disorder with different histological/molecular features. Among the different lung tumors, non‐small‐cell lung cancer (NSCLC) is the most represented histotype, characterized by various molecular markers, including the expression/overexpression of the fibroblast growth factor receptor‐1 (FGFR1). Thus, FGF/FGFR blockade by tyrosine kinase inhibitors (TKi) or FGF‐ligand inhibitors may represent a promising therapeutic approach in lung cancers. In this study we demonstrate the potential therapeutic benefit of targeting the FGF/FGFR system in FGF‐dependent lung tumor cells using FGF trapping (NSC12) or TKi (erdafitinib) approaches. The results show that inhibition of FGF/FGFR by NSC12 or erdafitinib induces apoptosis in FGF‐dependent human squamous cell carcinoma NCI‐H1581 and NCI‐H520 cells. Induction of oxidative stress is the main mechanism responsible for the therapeutic/pro‐apoptotic effect exerted by both NSC12 and erdafitinib, with apoptosis being abolished by antioxidant treatments. Finally, reduction of c‐Myc protein levels appears to strictly determine the onset of oxidative stress and the therapeutic response to FGF/FGFR inhibition, indicating c‐Myc as a key downstream effector of FGF/FGFR signaling in FGF‐dependent lung cancers.