FGFR families: biological functions and therapeutic interventions in tumors

Abstract

There are five fibroblast growth factor receptors (FGFRs), namely, FGFR1–FGFR5. When FGFR binds to its ligand, namely, fibroblast growth factor (FGF), it dimerizes and autophosphorylates, thereby activating several key downstream pathways that play an important role in normal physiology, such as the Ras/Raf/mitogen‐activated protein kinase kinase/extracellular signal‐regulated kinase, phosphoinositide 3‐kinase (PI3K)/AKT, phospholipase C gamma/diacylglycerol/protein kinase c, and signal transducer and activator of transcription pathways. Furthermore, as an oncogene, FGFR genetic alterations were found in 7.1% of tumors, and these alterations include gene amplification, gene mutations, gene fusions or rearrangements. Therefore, FGFR amplification, mutations, rearrangements, or fusions are considered as potential biomarkers of FGFR therapeutic response for tyrosine kinase inhibitors (TKIs). However, it is worth noting that with increased use, resistance to TKIs inevitably develops, such as the well‐known gatekeeper mutations. Thus, overcoming the development of drug resistance becomes a serious problem. This review mainly outlines the FGFR family functions, related pathways, and therapeutic agents in tumors with the aim of obtaining better outcomes for cancer patients with FGFR changes. The information provided in this review may provide additional therapeutic ideas for tumor patients with FGFR abnormalities.

Phylogenetic and transcriptomic characterization of insulin and growth factor receptor tyrosine kinases in crustaceans

“…InsR and EGFR were sister clades, as they shared furin-like repeat and leucine-rich repeat (Receptor L) domains in the N-terminal region ( Figures 1 , 3 , 6 ) ( 6 – 8 , 72 ). FGFR and PVR were clustered together, as they had immunoglobulin domains in the N-terminal region ( Figures 1 , 9 , 12 ) ( 6 , 9 , 11 , 72 ). This is consistent with the inferred evolutionary histories with the ancestral versions being and/or containing InsR and EGFR domains, and FGFR, PDGFR, and VEGFR constituting later evolved receptors ( 72 , 73 ).…”

“…EGFRs are characterized by L1 and L2 domains alternating with two furin-like cysteine-rich domains ( 6 , 8 , 14 ). FGFRs have three immunoglobulin-like domains (D1, D2, and D3), with a seven or eight amino acid “acid box” linking D1 and D2 ( 6 , 9 ). PDGFRs and VEGFRs are structurally related, which suggests a common origin.…”

Urinary Excretion of Biomolecules Related to Cell Cycle, Proliferation, and Autophagy in Subjects with Type 2 Diabetes and Chronic Kidney Disease

“…Hyperglycemia and oxidative stress are considered to be the primary factors activating the PI3K/AKT signaling in diabetes [ 13 , 14 , 85 ]. In addition, fibrogenic growth factors (TGF-β, CTGF) [ 14 , 16 , 32 ], elevated SIRT1 [ 34 , 35 ], decreased Klotho [ 26 ], PTEN [ 23 , 24 ], and BECN1 [ 86 ], as well as impaired FGF21 signaling [ 29 , 30 , 31 ], may contribute to the activation of the PI3K/AKT/mTOR pathway. A schematic representation of the role of PI3K/AKT/mTOR signaling in diabetic kidney disease is shown in Figure 2 .…”

“…Specifically, Klotho is required for the high-affinity binding of fibroblast growth factor (FGF) receptors with FGF19, FGF21, and FGF23 [ 28 ]. Consequently, FGF mediates the induction of the PI3K/AKT/mTOR signaling pathway [ 29 , 30 , 31 ]. The expression and effects of connective tissue growth factor (CTGF), a fibrotic mediator, also depend upon the PI3K/AKT/mTOR [ 32 , 33 ].…”

Hepatocellular carcinoma: signaling pathways, targeted therapy, and immunotherapy

“…Fibroblast growth factors (FGFs), named for their mitogenic ability of fibroblasts, often mediate metabolic function, tissue repair, and mature tissues regeneration by reactivating signaling pathways. 47 The FGF family consists of almost 20 ligands, which mainly exert their effects by binding to high‐affinity tyrosine kinase receptors encoded by four genes (FGFR1, FGFR2, FGFR3, and FGFR4) and activating downstream signaling pathways. 48 …”