Role of ErbB family receptor tyrosine kinases in intrahepatic cholangiocarcinoma

Table 3 Preclinical biological effects of ErbB RTK inhibitors alone or combined with other target-based treatments for biliary tract cancer cells

Agent	Target	Experimental condition	Biliary cancer cell line/tumor	Biological effects	Ref.
Gefitinib	EGFR	Cell culture	HAG-1 human gallbladder adenocarcinoma cell line	Dose-dependent in vitro cell growth inhibition by arresting cells in G0/G1, followed by progressive cell apoptosis; inhibition of EGFR phosphorylation and of Erk1/2 and Akt activation; decreased cyclin D1 mRNA and induced accumulation of p27 protein, a negative cell cycle regulator	[176]
Gefitinib + Ionizing radiation	EGFR	Cell culture	HuCCT1 human intrahepatic cholangiocarcinoma cell line; TFK-1 human bile duct carcinoma cell line	Gefitinib induced increase in radiosensitivity of HuCCT1 and TFK-1 cells	[177]
Cetuximab + erlotinib	EGFR	Cell culture and subcutaneous tumor xenografts in athymic nude mice	HuCCT1 cell line	Combined treatment with cetuximab blunted erlotinib-induced EGFR up-regulation and regulated in HuCCT1 growth inhibition and apoptosis in vitro and HuCCT1 tumor growth arrest in vivo	[178]
Gefitinib + CI-1040	EGFR + MEK-Erk1/2	Cell culture and subcutaneous tumor xenografts in athymic nude mice	HuCCT1 cell line	Drug combination significantly more effective than single agent treatments in suppressing both in vitro and in vivo tumor cell growth; combination treatment dramatically decreased phosphorylation levels of EGFR and Erk1/2 in cultured cells and in xenografted tumors, whereas HuCCT1 cells were found to be resistant to treatments with gefitinib or CI-1040 alone	[179]
Lapatinib	EGFR/ErbB2	Cell culture	Rat C611B and human HuCCT1 cholangiocarcinoma cell lines	Lapatinib was demonstrated to be a potent inhibitor of C611B and HuCCT1 cholangiocarcinoma cell growth in vitro by a mechanism involving inhibition of EGFR and ErbB2 activation, suppression of p42/44 MAPK and Akt phosphorylation, and induction of apoptosis	[180]
NVP-AEE788	EGFR/ErbB2 and VEGFR-2	Cell culture and subcutaneous tumor xenografts in athymic nude mice	EGI-1, TFK-1, CC-SW-1, CC-LP-1 and SK-ChA-1 human extrahepatic bile duct cancer cell lines; MZ-ChA-1 and MZ-CA-2 human gallbladder adenocarcinoma cell lines	NVP-AEE788 more efficacious than the EGFR RTK inhibitors gefitinib and erlotinib in suppressing in vitro cell growth; EGI-1 tumors in mice treated with NVP-AEE788 had significantly reduced volume and mass compared with those in placebo-treated mice, while erlotinib was without effect in inhibiting in vivo tumor growth; main mechanisms of NVP-AEE788 drug action were suppression of Erk1/2 phosphorylation, induced apoptosis, and inhibition of tumor angiogenesis	[181]
Emodin + Celecoxib	ErbB2 +COX-2	Cell culture	C611B rat intrahepatic cholangiocarcinoma cell line	Emodin and celecoxib combined to synergistically suppress anchorage-dependent and anchorage-independent cell growth in vitro through a mechanism involving enhanced inhibition of ErbB2 activation, decreased phospho-Akt, and enhanced caspase-9 and -3 activation, resulting in significantly increased apoptosis	[75]
Gefitinib or GW2974	EGFR	BK5.erbB2 transgenic mice constitutively expressing wild-type rat ErbB2	Gallbladder adenocarcinoma	Both agents produce significant chemopreventative and therapeutic effects in reducing gallbladder adenocarcinoma incidence, which was associated with prominent decreases in both the phosphorylation and protein levels of EGFR and ErbB2, with significantly decreased Erk1/2 acitivity and with a reduction in COX-2 protein levels in BK5.erbB2 mouse gallbladders	[182]
	EGFR/ErbB2

RTK: Receptor tyrosine kinase; EGFR: Epidermal growth factor receptor; VEGFR-2: Vascular endothelial growth factor receptor-2; COX-2: Cyclooxygenase-2.