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Page 2 of 11 Lee et al. Hepatoma Res 2018;4:52 I http://dx.doi.org/10.20517/2394-5079.2018.42

One signaling pathway that is increasingly recognized to play a role in the carcinogenesis of HCC is the fi-
broblast growth factor (FGF)/fibroblast growth factor receptor (FGFR) pathway, which has roles in oncogen-
[6,7]
esis, mediating cell proliferation and neo-angiogenesis . Preclinical models suggest that inhibition of the
[7]
FGFR pathway is a feasible therapeutic strategy and many clinical trials using FGF/FGFR pathway inhibi-
tors have since been conducted or are ongoing in hepatocellular carcinoma.

We attempt to review the importance of the FGF/FGFR pathway and current clinical evidence to date for use
of the pathway inhibitors in HCC.

FGF/FGFR PATHWAY AND ITS ABERRATIONS IN CANCER
The human FGF family consists of 22 structurally related molecules that interact with four FGFRs. Each
FGFR comprises three components, an extracellular domain which interacts with the FGF ligand, a trans-
membrane domain, and an intracellular domain. FGFs act as ligands which can bind to more than one kind
of FGFR, causing downstream activation of several pathways including the mitogen-activated protein kinase
pathway regulating cellular proliferation, and the phosphoinositide-3 kinase-Akt pathway controlling cellu-
[8]
[9]
lar survival . FGF/FGFR signaling is involved in normal embryonic development of the liver and lungs as
[10]
well as adult wound healing and angiogenesis .
FGFRs are widely expressed in adult tissue, although their relative levels differ in the various organ systems.
Under normal conditions, hepatocytes express high levels of FGFR3 and FGFR4 and have lower levels of
[11]
FGFR1 and FGFR2 .

FGFR signaling has significant effects on tumour neo-angiogenesis, both via the direct promotion of en-
[12]
dothelial cell proliferation through effects on the tumour microenvironment , as well as indirectly via
interactions and synergism with the vascular endothelial growth factor (VEGF) and platelet-derived growth
[13]
factor (PDGF) pathways .
FGFR pathway activation has also been shown to be an important resistance mechanism in response to
[15]
[16]
therapeutic pressure with use of anti-VEGF therapy [6,14] . In both the preclinical and clinical settings,
tumours progressing on anti-VEGF treatment have been shown to have a higher level of expression of FGF2.
As such, upfront dual inhibition of VEGFR and FGFR, or introduction of FGFR inhibition after progression
[17]
on a VEGF pathway inhibitor can potentially result in greater clinical benefit compared to inhibition of
the VEGF pathway alone.

FGFR aberrations occur in approximately 7% of all solid tumours and in almost every tumour type, though
[18]
[19]
the frequency and type of aberration differ . Pathway aberrations identified include : (1) gene amplifica-
tion, or post-transcriptional changes giving rise to receptor overexpression; (2) gene mutations, resulting in
constitutionally activated receptors or receptors that have a reduced dependence of ligand binding for activa-
tion; (3) translocations, resulting in expression of FGFR-fusion proteins with constitutive FGFR kinase activ-
ity; (4) alternative splicing of FGFR and isoform switching, changing ligand specificity and increasing the
range of FGFs that can activate the FGFR; (5) upregulation of FGF ligand expression.

Overall the most common aberration seen in solid tumours is FGFR gene amplification, most commonly in
FGFR1. FGFR mutations in cancer differ from those seen in hereditary disorders in that they are not limited
[19]
to the kinase domains, but may occur in any part of the gene .

RELEVANCE OF THE FGF PATHWAY IN HCC
The importance of the FGF/FGFR pathway in HCC can be seen in the fact that more than 80% of HCCs