Title:Targeting Drugs Against Fibroblast Growth Factor(s)-Induced Cell Signaling
Volume: 22
Issue: 2
Author(s): Shilpi Agrawal, Sanhita Maity, Zeina AlRaawi, Musaab Al-Ameer and Thallapuranam Krishnaswamy Suresh Kumar*
Affiliation:
- Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, Arkansas,United States
Keywords:
Fibroblast growth factor, fibroblast growth factor receptor, FGF/FGFR signaling, aberrant FGFR signaling, cancer.
Abstract:
Background: The fibroblast growth factor (FGF) family is comprised of 23 highly regulated
monomeric proteins that regulate a plethora of developmental and pathophysiological processes,
including tissue repair, wound healing, angiogenesis, and embryonic development. Binding of
FGF to fibroblast growth factor receptor (FGFR), a tyrosine kinase receptor, is facilitated by a glycosaminoglycan,
heparin. Activated FGFRs phosphorylate the tyrosine kinase residues that mediate
induction of downstream signaling pathways, such as RAS-MAPK, PI3K-AKT, PLCγ, and
STAT. Dysregulation of the FGF/FGFR signaling occurs frequently in cancer due to gene amplification,
FGF activating mutations, chromosomal rearrangements, integration, and oncogenic fusions.
Aberrant FGFR signaling also affects organogenesis, embryonic development, tissue homeostasis,
and has been associated with cell proliferation, angiogenesis, cancer, and other pathophysiological
changes.
Objective: This comprehensive review will discuss the biology, chemistry, and functions of FGFs,
and its current applications toward wound healing, diabetes, repair and regeneration of tissues, and
fatty liver diseases. In addition, specific aberrations in FGFR signaling and drugs that target FGFR
and aid in mitigating various disorders, such as cancer, are also discussed in detail.
Conclusion: Inhibitors of FGFR signaling are promising drugs in the treatment of several types of
cancers. The clinical benefits of FGF/FGFR targeting therapies are impeded due to the activation
of other RTK signaling mechanisms or due to the mutations that abolish the drug inhibitory activity
on FGFR. Thus, the development of drugs with a different mechanism of action for FGF/FGFR
targeting therapies is the recent focus of several preclinical and clinical studies.
