FGFR2-related pathogenesis and FGFR2-targeted therapeutics (Review)

Abstract

Abstract. FGFR2 gene at human chromosome 10q26 encodes FGFR2b and FGFR2c isoforms functioning as FGF receptors with distinct expression domain and ligand specificity. FGFR2 plays oncogenic and anti-oncogenic roles in a contextdependent manner. Single nucleotide polymorphisms (SNPs) within intron 2 of FGFR2 gene are associated with breast cancer through allelic FGFR2 upregulation. Missense mutations or copy number gains of FGFR2 gene occur in breast cancer and gastric cancer to activate FGFR2 signaling. Aberrant FGFR2 signaling activation induces proliferation and survival of tumor cells. The class switch from FGFR2b to FGFR2c occurs during progression of prostate cancer and bladder cancer because of spliceosome dysregulation. In addition, epidermal Fgfr2b knockout mice show increased sensitivity to chemical carcinogenesis partly due to the failure of Nfe2l2 (Nrf2)-mediated detoxification of reactive oxygen species (ROS). Loss of FGFR2b signaling induces epithelialto-mesenchymal transition (EMT) and unruly ROS. FGFR2 signaling dysregulation due to the accumulation of epigenetic modifications and genetic alterations during chronic inflammation, smoking, increased caloric uptake, and decreased exercise leads to carcinogenesis. PD173074, SU5402, AZD2171, and Ki23057 are small-molecule FGFR inhibitors. Human antibody, peptide mimetic, RNA aptamer, siRNA, and synthetic microRNA (miRNA) are emerging technologies to be applied for cancer therapeutics targeted to FGFR2. Because novel sequence technology and peta-scale supercomputer are opening up the sequence era following the genome era, personalized medicine prescribing targeted drugs based on germline and/or somatic genomic information is coming reality. Application of FGFR2 inhibitors for cancer treatment in patients with FGFR2 mutation or gene amplification is beneficial; however, that for cancer prevention in people with FGFR2 risk allele might be disadvantageous due to the impediment of a cytoprotective mechanism against oxidative stress.

Identification of fibroblast growth factor-8b target genes associated with early and late cell cycle events in breast cancer cells

“…Recent studies have linked the expression of certain FGFs and FGF receptors to tumorigenesis (Dorkin et al, 1999;Giri et al, 1999;Katoh and Katoh, 2009;Marzioni et al, 2009). …”

Fibroblast growth factor receptors in breast cancer: expression, downstream effects, and possible drug targets

“…In addition to the drugs described earlier, several other compounds targeting FGFRs are being tested on other types of cancer, including urothelial carcinoma, non-small-cell lung cancer, and ovarian cancer (Katoh & Katoh 2009, Antoniu & Kolb 2010, Turner & Grose 2010, Bello et al 2011, Lamont et al 2011. Even though most of these drugs are not specific for FGFRs, but also target PDGFRs and VEGFRs, this might actually be an advantage as these RTKs are known for their roles in tumor angiogenesis and proliferation (Petrelli & Giordano 2008).…”

“…First of all, numerous TKIs targeting FGFRs have been developed. These small molecules compete with ATP to bind to the receptor resulting in reduced activity of the kinase domain (Katoh & Katoh 2009, Turner & Grose 2010. However, as the kinase domains of RTKs are very similar, most TKIs are not specific for one FGFR and also inhibit the activity of VEGFRs and/or PDGFRs (Turner & Grose 2010).…”

“…The SNPs rs35054928 and rs2981578 are located next to an organic cation transporter (OCT)-binding site. The risk allele of rs2981578 also creates a putative binding site for runt-related transcription factor (RUNX) and the risk allele of rs10736303 one for ER (Katoh & Katoh 2009). The risk allele of rs7895676 has reduced binding capacity to CCAAT/ enhancer binding protein b (C/EBPb (CEBPB)).…”

“…Currently, RNA aptamers that target the FGFR2 kinase domain, the FRS2 interacting domain, and the extracellular domain of FGFR2 are being developed, but their effectiveness remains to be tested (Katoh & Katoh 2009). Therapeutic strategies using siRNA or miRNA are still in a very early stage of development focusing on off-target effects and delivery (Katoh & Katoh 2009). …”