FGFR-Driven Lung Cancer: Dissecting Resistance and Exploring Therapeutic Avenues.

Fibroblast growth factor receptors (FGFRs) are significant oncogenic contributors in lung cancer. The clinical development of FGFR-directed agents represents a promising advancement in precision oncology. However, their efficacy is substantially limited by the emergence of diverse resistance mechanisms. This review summarizes FGFR biology, genomic alterations, and signaling pathways in tumorigenesis. Nonselective tyrosine kinase inhibitors and selective FGFR inhibitors (including pan-FGFR and isoform-specific agents) have shown clinical activity in patients with FGFR-altered lung cancer. Moreover, resistance mechanisms, such as secondary FGFR mutations, bypass signaling, tumor microenvironment (TME) remodeling, and phenotypic switching, are discussed. Innovative approaches, including the second-generation FGFR TKIs, monoclonal antibodies (mAbs), FGF traps, antibody-drug conjugates, and synergistic combinations with immunotherapy or other receptor tyrosine kinase (RTK) inhibitors, are discussed to overcome resistance. Overall, this review offers theoretical insights and proposes strategies to tackle resistance to FGFR-directed treatments in lung cancer.