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Abstract
Fibroblast growth factor (FGF)/Fibroblast growth factor receptor (FGFR) signaling regulates various cellular processes during the embryonic development and in the adult organism. In the skin, fibroblasts and keratinocytes control proliferation and survival of melanocytes in a paracrine manner via several signaling molecules, including FGFs. FGF/FGFR signaling contributes to the skin surface expansion in childhood or during wound healing, and skin protection from UV light damage. Aberrant FGF/FGFR signaling has been implicated in many disorders, including cancer. In melanoma cells, the FGFR expression is low, probably because of the strong endogenous mutation-driven constitutive activation of the downstream mitogen-activated protein kinase-extracellular signal-regulated kinase (MAPK-ERK) signaling pathway. FGFR1 is exceptional as it is expressed in the majority of melanomas at a high level. Melanoma cells that acquired the capacity to synthesize FGFs can influence the neighboring cells in the tumor niche, such as endothelial cells, fibroblasts, or other melanoma cells. In this way, FGF/FGFR signaling contributes to intratumoral angiogenesis, melanoma cell survival, and development of resistance to therapeutics. Therefore, inhibitors of aberrant FGF/FGFR signaling are considered as drugs in combination treatment. The ongoing LOGIC-2 phase II clinical trial aims to find out whether targeting the FGF/FGFR signaling pathway with BGJ398 may be a good therapeutic strategy in melanoma patients who develop resistance to v-Raf murine sarcoma viral oncogene homolog B (BRAF)/MEK inhibitors.
Highlights
Receptor tyrosine kinases (RTKs) are cell membrane proteins comprising about 20 families with nearly 60 members
bromodomain and extra-terminal domain (BET) inhibitors could enhance Fibroblast Growth Factor Receptor (FGFR) expression in uveal melanoma (UM) cell lines and patient tumor samples, while FGFR inhibitors (AZD4547 and BLU9931) reversed the effects of stromal FGF2. These results strongly suggest that co-inhibition of the FGF2/FGFR signaling pathway is necessary to prevent the development of resistance and improve the efficacy of BET inhibitors [75]
The primary mechanism for abnormal signaling is connected with point mutations and chromosomal translocations that often result in constitutive dimerization and kinase activation of growth factor receptors, including FGFRs [92,93]
Summary
Receptor tyrosine kinases (RTKs) are cell membrane proteins comprising about 20 families with nearly 60 members. The common structure of cell membrane-localized FGFRs consists of a large ligand-binding extracellular region with three immunoglobulin-like (Ig-like) domains, a transmembrane helical region, and a cytoplasmic region with a catalytically active tyrosine kinase domain. Binding of FGFs to FGFRs is assisted by cofactors, heparin sulfate proteoglycans (HSPGs) in paracrine FGF signaling, or Klotho coreceptor in endocrine signaling [5] It triggers the dimerization of receptor monomers in the membrane and cross-autophosphorylation of tyrosine residues in the cytoplasmic kinase domain, which is followed by binding of various. Dabrafenib; DUSP, dual-specificity phosphatase; FRS2, FGFR substrate 2; GAB1, GRB2-associated binding protein 1; GRB2, growth factor receptor protein 2; JAK, Janus kinase; PKC, protein kinase C; PLC-γ, phospholipase C gamma; SOS, son of sevenless; SEF, similar expression to FGF; SPRY, Sprouty; STAT, signal transducer and activator of transcription; Tra, trametinib; Vem, vemurafenib. This review article summarizes the current knowledge on the fibroblast growth factor receptor signaling in skin cancers with a focus on melanoma
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