The efficacy of lapatinib to significantly suppress liver tumor growth was tested in an orthotopic, syngeneic rat model of intrahepatic cholangiocarcinoma progression. Our results demonstrated that simultaneous targeting of ErbB1 and ErbB2 signaling was significantly more effective in suppressing the in vitro growth of both rat and human cholangiocarcinoma cells than individual receptor targeting. Lapatinib was an even more potent inhibitor selleck screening library of cholangiocarcinoma cell growth and inducer of apoptosis than either tryphostin when tested in vitro against these respective cholangiocarcinoma
cell lines, regardless of differences in their levels of ErbB1 or ErbB2 protein expression and/or mechanism of activation. Lapatinib treatment also produced a significant suppression of intrahepatic cholangiocarcinoma growth when administered early to rats, but was without find more effect in inhibiting liver tumor growth in rats with more advanced tumors. Conclusion: Our findings suggest that simultaneous targeting of ErbB1 and ErbB2 could be a potentially selective strategy for cholangiocarcinoma therapy, but is likely to be ineffective by itself against advanced cancer. (HEPATOLOGY 2010) Overexpression of erythroblastic leukemia viral oncogene homolog (ErbB) receptor tyrosine kinases (TKs), most notably ErbB2 and ErbB1 (epidermal growth factor receptor)
has been demonstrated in both human and experimental selleck kinase inhibitor rodent cholangiocarcinoma cells.1 In addition, constitutive overexpression of activated ErbB2 has been shown to result in cholangiocarcinoma development in rodent models.1-3 Strategies to target ErbB receptor signaling may thus provide a useful new approach for the prevention or therapy of cholangiocarcinomas overexpressing ErbB1 and/or ErbB2 TK activity. In this context, the aims of this preclinical study were to: (1) assess if simultaneous targeting of ErbB1 and ErbB2 TKs produces a significantly greater concentration-dependent suppression of cholangiocarcinoma cell growth in both human and rat cholangiocarcinoma cell lines in culture
than that elicited by specific targeting of ErbB1 or ErbB2 signaling alone; (2) determine if select ErbB1 and ErbB2 TK inhibitors administered in combination act synergistically to enhance the growth inhibition of cultured cholangiocarcinoma cell lines expressing different levels of activated ErbB1 together with mutationally activated versus wild-type ErbB2; (3) establish molecular mechanisms for cholangiocarcinoma cell growth suppression in vitro that are associated with dual ErbB1/ErbB2 versus single receptor targeting; and (4) test the therapeutic potential of lapatinib (Tykerb; GW572016), a clinically relevant dual ErbB1/ErbB2 TK inhibitor approved for metastatic breast cancer therapy, in a syngeneic rat orthotopic cholangiocarcinoma model recently developed in our laboratory.