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Review
. 2015 Sep;34(3):479-96.
doi: 10.1007/s10555-015-9579-8.

Fibroblast growth factor receptor signaling in hereditary and neoplastic disease: biologic and clinical implications

Teresa Helsten  1 , Maria Schwaederle  2 , Razelle Kurzrock  3
Affiliations
Review

Fibroblast growth factor receptor signaling in hereditary and neoplastic disease: biologic and clinical implications

Teresa Helsten et al. Cancer Metastasis Rev. 2015 Sep.

Abstract

Fibroblast growth factors (FGFs) and their receptors (FGFRs) are transmembrane growth factor receptors with wide tissue distribution. FGF/FGFR signaling is involved in neoplastic behavior and also development, differentiation, growth, and survival. FGFR germline mutations (activating) can cause skeletal disorders, primarily dwarfism (generally mutations in FGFR3), and craniofacial malformation syndromes (usually mutations in FGFR1 and FGFR2); intriguingly, some of these activating FGFR mutations are also seen in human cancers. FGF/FGFR aberrations reported in cancers are mainly thought to be gain-of-function changes, and several cancers have high frequencies of FGFR alterations, including breast, bladder, or squamous cell carcinomas (lung and head and neck). FGF ligand aberrations (predominantly gene amplifications) are also frequently seen in cancers, in contrast to hereditary syndromes. There are several pharmacologic agents that have been or are being developed for inhibition of FGFR/FGF signaling. These include both highly selective inhibitors as well as multi-kinase inhibitors. Of note, only four agents (ponatinib, pazopanib, regorafenib, and recently lenvatinib) are FDA-approved for use in cancer, although the approval was not based on their activity against FGFR. Perturbations in the FGFR/FGF signaling are present in both inherited and malignant diseases. The development of potent inhibitors targeting FGF/FGFR may provide new tools against disorders caused by FGF/FGFR alterations.

Keywords: Cancer; Cancer therapy; FGF; FGFR; Genetics.

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Figures

Fig. 1
Fig. 1
FGF/FGFR activation in cancer and inhibitors. a The activation of FGF/FGFR signaling in cancer. The structure of FGF/FGFR comprises two receptor molecules, two FGFs, and one heparan sulfate proteoglycan chain. The FGFRs are formed by three immunoglobulin domains (IgI–III), a transmembrane helix, and intracellular tyrosine kinase domains. The mechanisms driving FGF signaling in cancer can be divided into two categories: first, genomic alterations of FGFR that can lead to ligand-independent receptor signaling and, second, alterations that support a ligand-dependent signaling activation. Following FGF binding to FGFR and heterodimerization, the tyrosine kinase domains phosphorylate each other, leading to the activation of key downstream pathways. b Examples of FGF/FGFR inhibitors; asterisk denotes FDA-approved drugs in cancer; Ab = Antibody; FP-1039 (GSK3052230) is a ligand trap, i.e., sequesters FGFs and inhibits their signaling [71]. c The interactions between FGFs and FGFRs; references: Guillemot et al. [32], Powers et al. [191], Ornitz et al. [192], Zhang et al. [34]. Interaction between FGF ligands and receptors is an evolving field; variability may be observed between studies and tissue types. 1FGF11-14 are not ligands for FGFRs and are known as FGF homologous factors (FHF1–4)[28, 29]. There is no human FGF15
Fig. 2
Fig. 2
Approximate frequencies of FGFR alterations in diverse cancers. Data was extracted/analyzed based on cbioportal at http://www.cbioportal.org/public-portal (accessed November 2014). Most of the studies included >200 patients. Alterations in FGFR1, FGFR2, FGFR3, and FGFR4 were included. Please refer to Table 3 for more details and additional references. Abbreviations: FGFR = fibroblast growth factor receptor
Fig. 3
Fig. 3
Approximate frequencies of FGF ligand alterations in diverse cancers. Data was extracted/analyzed based on data from cbioportal at http://www.cbioportal.org/public-portal (accessed November 2014). Cervical cancer included squamous cell carcinoma and endocervical adenocarcinoma. Please refer to Table 4 for more details and additional references. Abbreviations: FGF = fibroblast growth factor
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