Fibroblast growth factor receptor 1–4 (FGFR1–4) (FGFR1–4)

Fibroblast growth factor receptors 1–4 (FGFR1–4) are a family of four highly conserved receptor tyrosine kinases that play a fundamental role in regulating essential cellular processes, including proliferation, differentiation, migration, and survival (Krook et al., 2021 [9]). These receptors are activated by the binding of fibroblast growth factor (FGF) ligands, which induces receptor dimerization and subsequent trans-autophosphorylation of the intracellular kinase domain (Dai et al., 2019 [16]). This activation triggers several downstream signaling cascades, such as the MAPK/ERK, PI3K/AKT, and PLCγ pathways, which are critical for embryonic development, tissue repair, and metabolic homeostasis (Katoh & Nakagama, 2014 [2]). Dysregulation of FGFR signaling, often through gene amplification, activating mutations, or chromosomal translocations resulting in oncogenic fusions, is a frequent driver in various malignancies, including urothelial carcinoma, cholangiocarcinoma, and breast cancer (Meric-Bernstam et al., 2022 [1]). Activating alterations in FGFR1–4 are found in approximately 7% of all human cancers, making them significant therapeutic targets (Helsten et al., 2016 [11]). Consequently, several FDA-approved pan-FGFR and selective inhibitors, such as erdafitinib and pemigatinib, have been developed to treat patients with specific FGFR aberrations (Loriot et al., 2019 [2]). However, therapeutic use of these inhibitors is often associated with specific class-effect toxicities, most notably hyperphosphatemia due to FGFR1 inhibition in the kidneys and ocular complications like serous retinopathy (Babina & Turner, 2017 [2]). The emergence of secondary resistance mutations in the kinase domain, such as gatekeeper mutations, remains a major clinical challenge in the long-term efficacy of FGFR-targeted therapies (Krook et al., 2021 [9]).

Other names

FGFR1FGFR2FGFR3FGFR4CD331CD332CD333CD334BFGFRCEKFLGFLT2HBGFRBEKBFR-1CEK3CFD1ECT1JTK14KGFRTK14TK25ACHCEK2JTK4JTK2TKF

FGFR inhibitors typically function as ATP-competitive small molecules that bind to the intracellular tyrosine kinase domain of FGFR1–4. This binding prevents the autophosphorylation of the receptor and the subsequent recruitment of adapter proteins like FRS2, thereby blocking the activation of downstream oncogenic signaling pathways such as MAPK/ERK, PI3K/AKT, and STAT (Dai et al., 2019 [16]; Krook et al., 2021 [9]).