Current progress in cancer treatment by targeting FGFR signaling

Fibroblast growth factor receptors (FGFRs), a family of transmembrane receptors with intracellular tyrosine kinase domains, and fibroblast growth factors (FGFs) form the FGF/FGFR signaling pathways, which participate in cell development, differentiation, cell survival, migration, angiogenesis, and carcinogenesis. The FGF/FGFR family consists of 4 FGFRs and 22 ligands (FGFs). FGFR binding to cognate ligands induces receptor dimerization and intracellular phosphorylation of receptor kinase domains. As a result, four downstream intracellular pathways are triggered: RASRAF-MEK-MAPK; PI3K-AKT-mTOR; JAK-STAT; and PLC gamma (Figure 1). Overactivation of the RAS-RAF-MEK-MAPK pathway stimulates cell proliferation and differentiation, while PI3K-AKT-mTOR pathway overactivation inhibits apoptosis. The JAK-STAT pathway promotes tumor invasion and metastasis, and enhances tumor immune evasion. The PLC gamma signaling pathway has an important role in regulating tumor cell metastasis. Alterations in FGFR genes, including gene amplification, activating mutations, rearrangements, and fusions, can result in excessive activation of the FGFR signaling pathway and further induce normal cell carcinogenesis. In this review we summarize the types of FGFR aberrations and advances in drugs targeting the FGF/FGFR pathway. We also comment on potentially effective strategies and current obstacles in antiFGFR therapy.