FGFR2

FGFRs are transmembrane, receptor tyrosine kinases (RTK) consisting of three extracellular immunoglobulin-like domains and one intracellular split tyrosine kinase domain (PMID: 20094046). FGFs are secreted glycoproteins that are readily sequestered by the extracellular matrix and the cell surface by heparan sulfate proteoglycans (HPSG), which stabilize the FGF–FGFR interaction by protecting FGFs from protease-mediated degradation. The binding of an FGF to an FGFR leads to receptor dimerization and transphosphorylation of tyrosine kinase domains (PMID: 23418312, PMID: 26078430). There are 23 different fibroblast growth factor (FGF) 1-23 ligands that bind to FGFR. Binding of FGF ligands to FGFR 1-4 activates the downstream signaling pathways including mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K)–protein kinase B (AKT), and signal transducer and activator of transcription (STAT) thereby regulating various cellular processes and cell cycle (PMID: 23696246, PMID: 25772309). FGFR can drive physiological functions such as embryogenesis, bile acid synthesis, angiogenesis, wound repair, tissue and phosphate homeostasis. The pathway also plays a key role in cellular functions including migration, proliferation (mitogenesis), and apoptosis thereby regulating various oncogenic pathways (PMID: 20094046). Gene amplification abnormalities are most commonly reported in FGFR1and FGFR4 whereas FGFR2 and FGFR3 are most commonly implicated in fusions. Apart from genomic aberrations in FGFR genes, paracrine effect of FGFs released from tumor cells and stroma promote tumorigenesis (PMID: 19508171). In addition to down-regulated FGFR2 expression in some genitourine-system tumors, up-regulated FGFR2 expression has been found in gastric cancer, pancreatic cancer, breast cancer, cholangiocarcinoma and lung cancer. The reasons for the difference in FGFR2 expression and action in different tumors are still unclear, and may be related to the tumor microenvironment (PMID: 24229629, PMID: 31899106).

First-generation FGFR-TKI operate as multi-target inhibitors, the kinase domains of the FGFR, VEGFR and platelet-derived growth factor receptor (PDGFR) families are phylogenetically related, and several non-selective TKIs originally developed to inhibit VEGFRs also inhibit FGFR in vitro, such as ponatinib, brivanib, nintedanib, lenvatinib, dovitinib, and lucitanib. Although simultaneous inhibition of multiple RTKs may increase treatment efficacy by concomitant disturbance of redundant pathways, increased side effects also arise, and lack of bioactivity against FGFRs may limit their efficacy in tumors with aberrant FGFR signaling. Selective inhibitors can specifically target fgFR-specific tyrosine kinase domains with better efficacy and fewer side effects. Erdafitinib is the first FGFR-targeted drug to be marketed for the treatment of advanced bladder cancer with specific FGFR2/3 mutations (PMID: 31461086) that binds and inhibits enzyme activity and reduces cell activity. Pemigatinib, the first targeted agent for cholangiocarcinoma approved by the FDA, targets FGFR1/2/3 and inhibits kinase activity (PMID: 33034201). Derazantinib is approved for the treatment of FGFR2 gene fusion positive patients and is currently approved in China. Zoligratinib (Debio 1347) is an FGFR1, FGFR2 and FGFR3 inhibitor, was granted fast track designation to Debio 1347 for the treatment of patients with unresectable or metastatic tumors with specific FGFR gene alterations by FDA. Infigratinib (BGJ398) is an orally bioavailable, selective pan-FGFR kinase inhibitor, has shown preliminary clinical activity against tumors with FGFR alterations (PMID: 29182496, NCT03773302). In addition, Monoclonal antibodies (mAb) targeting FGFs or FGFRs can block FGFR signaling by interfering with ligand binding or receptor dimerization, FP-1039 is a soluble fusion protein consisting of the extracellular domain of FGFR1c fused to the Fc region of IgG1 that prevents binding of FGF1, FGF2, and FGF4 (PMID: 26646757). MFGR1877S is a human anti-FGFR3 mAb that showed antitumor activity in preclinical models of bladder cancer with FGFR3 overexpression (NCT01122875).