On the other hand, the significantly smaller-sized cholangiocarcinomas, dissected from rat liver after 24 days of lapatinib treatment initiated on day 2 showed neoplastic ductal structures that were more morphologically differentiated and expressing a more strongly positive immunoreactivity for phospho-ErbB2Tyr1248 than those observed in the more progressed tumors check details harvested at the same time from the vehicle-treated control rats (Supporting Fig. 2A,B). No differences in tumor histopathology nor phospho-ErbB2Tyr1248 immunoreactivity were noted

between tumors analyzed from the day 8 lapatinib-initiated treatment group versus those from the corresponding vehicle control group. To date, only a very limited number of preclinical and clinical studies aimed at testing if dual ErbB1/ErbB2 targeting may have a potential value as a treatment for cholangiocarcinoma have been reported. Weidmann et al.11 previously demonstrated the dual ErbB1/ErbB2 inhibitor NVP-AEE778, which also exhibited anti–vascular endothelial growth factor receptor-2 activity, to be more efficacious than the single ErbB1 inhibitors gefitinib and erlotinib in suppressing the in vitro HSP inhibitor cancer growth of seven different human cholangiocarcinoma cell lines. In vivo treatment with NVP-AEE788 was also shown to

significantly reduce the volume of tumors formed in nude mice after subcutaneous injection of EGl-1 cholangiocarcinoma cells. Kiguchi et al.12 further reported that gefitinib, as well as the dual ErbB1/ErbB2 TK inhibitor, GW2974, each acted as potent chemopreventive and therapeutic agents when tested in a transgenic mouse model of gallbladder carcinoma constitutively overexpressing

wild-type rat ErbB2 along with elevated ErbB1 MCE公司 protein and phosphotyrosine levels.2 In contrast, in a recent phase 2 study of the dual ErbB1/ErbB2 TK inhibitor lapatinib in patients with advanced biliary tree cancer, no objective therapeutic responses were reported and lapatinib did not show activity.13 Thus, we were prompted to further assess preclinically the potential of dual ErbB1/ErbB2 targeting to enhance growth suppression of cholangiocarcinoma cell lines expressing varying levels of ErbB1 and ErbB2, as well as in an orthotopic, syngeneic rat model of intrahepatic cholangiocarcinoma progression mimicking pathological and clinical features of the advanced human disease. Reported frequencies of ErbB2 overexpression detected by semiquantitative immunohistochemistry in the cancerous epithelium of formalin-fixed, paraffin-embedded human biliary tract adenocarcinomas have varied widely, ranging between 0% and 82% for analyzed cohorts of intrahepatic cholangiocarcinomas1, 8 and between 5.1% and 86% for extrahepatic cholangiocarcinomas.