BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is the third leading cause of 
cancer death. Although sorafenib has been shown to improve survival of patients 
with advanced HCC, this improvement is modest and patients eventually have 
refractory disease. This study aims at investigating the antitumor, 
antiangiogenesis and antimetastatic activities of dovitinib in preclinical 
models of HCC.
METHODS: 21-0208 and SK-HEP1 cells as well as patient-derived HCC models were 
employed to study the antitumor effect of dovitinib. Changes of biomarkers 
relevant to FGFR/VEGFR/PDGFR pathways were determined by Western blotting. 
Microvessel density, apoptosis and cell proliferation were analyzed by 
immunohistochemistry.
RESULTS: Treatment of SK-HEP1 cells with dovitinib resulted in G2/M cell cycle 
arrest, inhibition of colony formation in soft agar and blockade of bFGF-induced 
cell migration. Dovitinib inhibited basal expression and FGF-induced 
phosphorylation of FGFR-1, FRS2-α and ERK1/2. In vivo, dovitinib potently 
inhibited tumor growth of six HCC lines. Inhibition of angiogenesis correlated 
with inactivation of FGFR/PDGFR-β/VEGFR-2 signaling pathways. Dovitinib also 
caused dephosphorylation of retinoblastoma, upregulation of p-histone H2A-X and 
p27, and downregulation of p-cdk-2 and cyclin B1, which resulted in a reduction 
in cellular proliferation and the induction of tumor cell apoptosis. In an 
orthotopic model, dovitinib potently inhibited primary tumor growth and lung 
metastasis and significantly prolonged mouse survival.
CONCLUSIONS: Dovitinib demonstrated significant antitumor and antimetastatic 
activities in HCC xenograft models. This study provides a compelling rationale 
for clinical investigation in patients with advanced HCC.