Hepatocellular carcinoma (HCC) often displays resistance to recombinant tumor 
necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. 
Dovitinib, a multiple tyrosine kinase inhibitor, and tigatuzumab, a novel 
humanized anti-human death receptor 5 (DR5) agonistic antibody, are both under 
clinical investigations in HCC. Here, we report that dovitinib sensitizes 
resistant HCC cells to TRAIL- and tigatuzumab-induced apoptosis through 
inhibition of signal transducers and activators of transcription 3 (STAT3). Our 
data indicate that HCC cells showed significant resistance to TRAIL- and 
tigatuzumab-induced apoptosis. The combination of dovitinib and tigatuzumab 
restored the sensitivity of HCC cells to TRAIL- and tigatuzumab-induced 
apoptosis. Dovitinib down-regulated phospho-STAT3 (Tyr705) (p-STAT3) and 
subsequently reduced the protein levels of STAT3-regulated proteins, Mcl-1, 
survivin and cylcin D1, in TRAIL-treated HCC cells. Knockdown of STAT3 by 
RNA-interference overcame apoptotic resistance to TRAIL in HCC cells, and 
ectopic expression of STAT3 in HCC cells abolished the sensitizing effect of 
dovitinib on TRAIL-induced apoptosis. Importantly, silencing SHP-1 by 
RNA-interference reduced the effects of dovitinib and TRAIL on p-STAT3 and 
apoptosis, whereas co-treatment of TRAIL and dovitinib increased the activity of 
SHP-1. Moreover, in vivo the combination of tigatuzumab and dovitinib inhibited 
Huh-7 xenograft tumor growth. In conclusion, dovitinib sensitizes resistant HCC 
cells to TRAIL- and tigatuzumab-induced apoptosis through a novel machinery: 
SHP-1 dependent STAT3 inhibition.