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Lee et al. Hepatoma Res 2018;4:52 I http://dx.doi.org/10.20517/2394-5079.2018.42 Page 3 of 11

[20]
[21]
overexpress at least one FGF and/or FGFR . The main FGFRs expressed in liver tissue are FGFR3 and
[22]
FGFR4 .
Whilst healthy hepatocytes express minimal levels of FGF1 or FGF2, these levels increase when there is cir-
rhosis and increasing levels correlate with the progression of cirrhosis into HCC. Higher levels of FGF1 and
[23]
FGF2 are also seen in more advanced tumour stages . There is hence interest in using FGF1 and FGF2 ex-
[24]
pression levels as a prognostic marker , though its utility as a diagnostic marker or for follow-up of HCC
[25]
patients is limited by its non-specificity .
[26]
In preclinical models, FGF1 and FGF2 were shown to stimulate proliferation of HCC cell lines through the
[27]
activation of tumour invasion and angiogenesis resulting in an increase in capillarised sinusoids . There is
however substantial redundancy in FGF1- and FGF2-mediated signaling, suggesting that direct targeting of
[28]
these ligands may have limited therapeutic efficacy .
The FGF8 subfamily, comprising FGFs 8, 17 and 18, also promotes oncogenesis through stimulating hepato-
cyte proliferation. At least one member of the FGF8 subfamily or its corresponding receptors FGFR2, FGFR3
[20]
and FGFR4 is upregulated in more than 50% of HCCs . The use of small interfering RNA (siRNA) target-
[20]
ing FGF18 has been shown to reduce the viability and proliferation of HCC cells .
The FGF19 subfamily, comprising FGFs 19, 21 and 23, act as endocrine factors mediating metabolic effects
through FGFR signaling. FGF19, which comes mainly from the ileum, plays a role in the physiological regu-
lation of bile acid and cholesterol metabolism as well as insulin sensitivity. FGF19 binds exclusively to FGFR4
with the co-receptor β-Klotho (KLB) stabilising the interaction. FGF19/FGFR4 signaling is thought to be of
[29]
particular importance in the carcinogenesis of HCC , with FGF19 expression increased, through focal am-
[30]
plification of 11q, in approximately 6%-12% of HCC cases . FGFR4 expression is also upregulated in almost
[31]
half of HCCs . In addition, FGF19 levels may be prognostic, with higher expression in resected HCC speci-
[32]
mens being associated with larger tumour size and stage and higher risk of recurrence after hepatectomy .
[29]
[33]
In vitro studies show that FGF19 induces HCC cell proliferation and inhibits apoptosis . Mice models
also confirm that the ectopic expression of FGF19 promotes hepatocyte proliferation, dysplastic change and
[34]
precipitates the formation of HCC . Similarly, FGFR4 knockout mice showed increased hepatocyte injury
[35]
when challenged with the hepato-toxin carbon tetrachloride . Targeting the FGF19/FGFR4 interaction
through various approaches appears to be effective in inhibiting hepatocarcinogenesis and HCC growth
[36]
in preclinical models, be it through the use of a neutralizing antibody against FGF19 , through genetic
[33]
[30]
knockdown , or though siRNA . Using siRNA to knockdown FGFR4 also showed similar results in mice
[37]
models, which had impaired regeneration and increased liver injury after partial hepatectomy .
As previously mentioned, the FGF/FGFR pathway has been shown to be upregulated after initial blockade of
[38]
the anti-VEGF pathway , and may be an important resistance mechanism to anti-VEGF therapy including
that of sorafenib. For a long time, sorafenib was the only systemic treatment option for advanced HCC, hav-
ing demonstrated an improvement in overall survival of 2-3 months in two large phase III trials [39,40] . Whilst
having inhibitory effects on multiple targets including VEGFR, PDGFR and Raf kinases, sorafenib has no
[41]
anti-FGFR activity . Concomitant dual blockade of FGF/FGFR and VEGF pathways are hence a potentially
[38]
attractive approach in the efforts to overcome this resistance .

OVERVIEW OF FGF/FGFR PATHWAY INHIBITORS AND THEIR TOXICITIES
Current available inhibitors against the FGF/FGFR pathway can be classified into Figure 1: (1) monoclonal
antibodies which competitively inhibit FGF binding to the FGFR extracellular domain; (2) FGF-ligand traps;
and (3) small molecule tyrosine kinase inhibitors (FGFR TKIs).