scholarly journals Fibroblast Growth Factor Receptor 4 Targeting in Cancer: New Insights into Mechanisms and Therapeutic Strategies

Cells ◽  
2019 ◽  
Vol 8 (1) ◽  
pp. 31 ◽  
Author(s):  
Liwei Lang ◽  
Yong Teng
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Hematologic Malignancies ◽  
Future Research ◽  
Tyrosine Kinase Receptor ◽  
Fibroblast Growth ◽  
Therapeutic Implications ◽  
And Function

Fibroblast growth factor receptor 4 (FGFR4), a tyrosine kinase receptor for FGFs, is involved in diverse cellular processes, including the regulation of cell proliferation, differentiation, migration, metabolism, and bile acid biosynthesis. High activation of FGFR4 is strongly associated with the amplification of its specific ligand FGF19 in many types of solid tumors and hematologic malignancies, where it acts as an oncogene driving the cancer development and progression. Currently, the development and therapeutic evaluation of FGFR4-specific inhibitors, such as BLU9931 and H3B-6527, in animal models and cancer patients, are paving the way to suppress hyperactive FGFR4 signaling in cancer. This comprehensive review not only covers the recent discoveries in understanding FGFR4 regulation and function in cancer, but also reveals the therapeutic implications and applications regarding emerging anti-FGFR4 agents. Our aim is to pinpoint the potential of FGFR4 as a therapeutic target and identify new avenues for advancing future research in the field.

scholarly journals Novel Regulatory Factors and Small-Molecule Inhibitors of FGFR4 in Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Yanan Liu ◽  
Canwei Wang ◽  
Jifa Li ◽  
Jiandong Zhu ◽  
Chengguang Zhao ◽  
...  
Keyword(s):  
Growth Factor ◽  
Ligand Binding ◽  
Fibroblast Growth Factor ◽  
Small Molecule ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Cancer Development ◽  
Tyrosine Kinase Receptor ◽  
Fibroblast Growth ◽  
Receptor Family

Fibroblast growth factor receptor 4 (FGFR4) is a tyrosine kinase receptor that is a member of the fibroblast growth factor receptor family and is stimulated by highly regulated ligand binding. Excessive expression of the receptor and its ligand, especially FGF19, occurs in many types of cancer. Abnormal FGFR4 production explains these cancer formations, and therefore, this receptor has emerged as a potential target for inhibiting cancer development. This review discusses the diverse mechanisms of oncogenic activation of FGFR4 and highlights some currently available inhibitors targeting FGFR4.

An important role for the IIIb isoform of fibroblast growth factor receptor 2 (FGFR2) in mesenchymal-epithelial signalling during mouse organogenesis

Development ◽  
2000 ◽  
Vol 127 (3) ◽  
pp. 483-492 ◽  
Author(s):  
L. De Moerlooze ◽  
B. Spencer-Dene ◽  
J. Revest ◽  
M. Hajihosseini ◽  
I. Rosewell ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Tyrosine Kinase Receptor ◽  
Fibroblast Growth ◽  
Developmental Abnormalities ◽  
Receptor Proteins ◽  
Early Organogenesis ◽  
Skull Formation

The fibroblast growth factor receptor 2 gene is differentially spliced to encode two transmembrane tyrosine kinase receptor proteins that have different ligand-binding specificities and exclusive tissue distributions. We have used Cre-mediated excision to generate mice lacking the IIIb form of fibroblast growth factor receptor 2 whilst retaining expression of the IIIc form. Fibroblast growth factor receptor 2(IIIb) null mice are viable until birth, but have severe defects of the limbs, lung and anterior pituitary gland. The development of these structures appears to initiate, but then fails with the tissues undergoing extensive apoptosis. There are also developmental abnormalities of the salivary glands, inner ear, teeth and skin, as well as minor defects in skull formation. Our findings point to a key role for fibroblast growth factor receptor 2(IIIb) in mesenchymal-epithelial signalling during early organogenesis.

scholarly journals Fibroblast Growth Factor Receptor 3 (FGFR3) Is a Strong Heat Shock Protein 90 (Hsp90) Client

2011 ◽  
Vol 286 (22) ◽  
pp. 19597-19604 ◽  
Author(s):  
Melanie B. Laederich ◽  
Catherine R. Degnin ◽  
Gregory P. Lunstrum ◽  
Paul Holden ◽  
William A. Horton
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor Receptor ◽  
Genetic Diseases ◽  
Growth Factor Receptor ◽  
Heat Shock Protein 90 ◽  
Fibroblast Growth ◽  
Hsp90 Inhibition ◽  
The Stability ◽  
And Function

Fibroblast growth factor receptor 3 (FGFR3) is a key regulator of growth and differentiation, whose aberrant activation causes a number of genetic diseases including achondroplasia and cancer. Hsp90 is a specialized molecular chaperone involved in stabilizing a select set of proteins termed clients. Here, we delineate the relationship of Hsp90 and co-chaperone Cdc37 with FGFR3 and the FGFR family. FGFR3 strongly associates with these chaperone complexes and depends on them for stability and function. Inhibition of Hsp90 function using the geldanamycin analog 17-AAG induces the ubiquitination and degradation of FGFR3 and reduces the signaling capacity of FGFR3. Other FGFRs weakly interact with these chaperones and are differentially influenced by Hsp90 inhibition. The Hsp90-related ubiquitin ligase CHIP is able to interact and destabilize FGFR3. Our results establish FGFR3 as a strong Hsp90 client and suggest that modulating Hsp90 chaperone complexes may beneficially influence the stability and function of FGFR3 in disease.

scholarly journals A Pancancer Analysis of the Expression Landscape and Clinical Relevance of Fibroblast Growth Factor Receptor 2 in Human Cancers

2021 ◽  
Vol 11 ◽  
Author(s):  
Juanni Li ◽  
Kuan Hu ◽  
Jinzhou Huang ◽  
Lei Zhou ◽  
Yuanliang Yan ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor Receptor ◽  
Therapeutic Targets ◽  
Growth Factor Receptor ◽  
Fibroblast Growth ◽  
Genetic Aberrations ◽  
Therapeutic Implications ◽  
Clinical Associations

Background: Fibroblast growth factor receptor 2 (FGFR2) is frequently altered in tumors and one of the top therapeutic targets in cholangiocarcinoma (CHOL) with FGFR2 fusions. Although there have been several studies on individual tumors, a comprehensive analysis of FGFR2 genetic aberrations and their simultaneous clinical implications across different tumors have not been reported.Methods: In this study, we used the large comprehensive datasets available, covering over 10,000 tumor samples across more than 30 cancer types, to analyze FGFR2 abnormal expression, methylation, alteration (mutations/fusions and amplification/deletion), and their clinical associations.Results: Alteration frequency, mutation location distribution, oncogenic effects, and therapeutic implications varied among different cancers. The overall mutation rate of FGFR2 is low in pancancer. CHOL had the highest mutation frequency, and fusion accounted for the major proportion. All these fusion aberrations in CHOL were targetable, and an FDA-approved drug was approved recently. Uterine corpus endometrial carcinoma (UCEC) had the highest number of FGFR2 mutations, and the most frequently mutated positions were S252W and N549K, where the functional impact was oncogenic, but targeted therapy was less effective. Additionally, DNA methylation was associated with FGFR2 expression in several cancers. Moreover, FGFG2 expression and genetic aberrations showed clinical associations with patient survival in several cancers, indicating their potential for application as new tumor markers and therapeutic targets.Conclusions: This study showed the full FGFR2 alteration spectrum and provided a broad molecular perspective of FGFR2 in a comprehensive manner, suggesting some new directions for clinical targeted therapy of cancers.

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