Structural Alterations in Human Fibroblast Growth Factor Receptors in Carcinogenesis

Abstract

Fibroblast growth factor (FGF) plays an important role in human embryogenesis, angiogenesis, cell proliferation, and differentiation. Carcinogenesis is accompanied by aberrant constitutive activation of FGF receptors (FGFRs) resulting from missense mutation in the FGFR1-4 genes, generation of chimeric oncogenes, FGFR1-4 gene amplification, alternative splicing shift toward formation of mesenchymal FGFR isoforms, and FGFR overexpression. Altogether, these alterations contribute to auto- and paracrine stimulation of cancer cells and neoangiogenesis. Certain missense mutations are found at a high rate in urinary bladder cancer and can be used for non-invasive cancer recurrence diagnostics by analyzing urine cell pellet DNA. Chimeric FGFR1/3 and amplified FGFR1/2 genes can predict cell response to the targeted therapy in various oncological diseases. In recent years, high-throughput sequencing has been used to analyze exomes of virtually all human tumors, which allowed to construct phylogenetic trees of clonal cancer evolution with special emphasis on driver mutations in FGFR1-4 genes. At present, FGFR blockers, such as multi-kinase inhibitors, specific FGFR inhibitors, and FGF ligand traps are being tested in clinical trials. In this review, we discuss current data on the functioning of the FGFR family proteins in both normal and cancer cells, mutations in the FGFR1-4 genes, and mechanisms underlying their oncogenic potential, which might be interesting to a broad range of scientists searching for specific tumor markers and targeted anti-cancer drugs.

FGFR-TKI resistance in cancer: current status and perspectives

“…It plays a role in regulating excessive activation of the FGF-FGFR1 signaling pathway [ 4 , 5 ]. The signaling axis of FGFRs is primarily activated in a ligand-dependent manner, by binding of fibroblast growth factors (FGFs) and the subsequent receptor dimerization induced intracellular kinase transautophosphorylation events [ 6 ]. Meanwhile, FGFRs can also be activated in a ligand-independent manner, such as chromosome translocation induced FGFRs gene fusion with other constitutively expressed genes [ 7 ].…”

Advances of Fibroblast Growth Factor/Receptor Signaling Pathway in Hepatocellular Carcinoma and its Pharmacotherapeutic Targets

“…The specific interaction of FGFs-FGFRs with cofactors activates several intracellular cascades, including Ras/MAPK, PI3K/Akt, and PLCγ/PKC pathways, to regulate target genes transcription (Katoh and Nakagama, 2014). Abnormalities of FGFs/FGFRs will lead to many diseases and are considered as a risk factor in the development of cancer (Itoh, 2010;Touat et al, 2015;Mikhaylenko et al, 2018). The gene transcription level (Figure 1A) and mutation status of (Figure 1B) FGFs/FGFRs were also investigated in HCC patients based on GEPIA2 and cBioPortal database (Cerami et al, 2012;Gao et al, 2013;Tang et al, 2017;Tang et al, 2019).…”

“…The FGF19 subfamily consists of FGF15/19, FGF21, and FGF23. Although Fgf15/19, FGF21, and FGF23 have only about 22-35% amino acid identity, phylogenetic and gene locus analyses suggested that they belong to one subfamily Ornitz, 2004, 2008;Mikhaylenko et al, 2018). FGF15 and FGF19 are the mouse and human orthologs, respectively, which share 53% amino acid homology.…”

Advanced technological tools to study multidrug resistance in cancer

“…Although differences between CTC and ctDNA genotyping and discordant genotypes between tumor biopsy and blood-based analyses were recognized, these disagreements are due to the methodological differences in isolation (Schechter et al, 2015;Sundaresan et al, 2016). Thus, it is known that the DNA isolation for a liquid biopsy varies due to tumor-specific mutations in DNA isolated from other cells present in the urine or the fluid itself (Mikhaylenko et al, 2018).…”