Overexpression of
epidermal growth factor receptor (ErbB1) and/or ErbB2 has been implicated in the pathogenesis of
cholangiocarcinoma, suggesting that combined ErbB1/ErbB2 targeting might serve as a target-based therapeutic strategy for this highly lethal
cancer. To test this strategy, we investigated targeting with the ErbB1 inhibitor tryphostin AG1517 and the ErbB2 inhibitor tryphostin
AG879, in combination and alone, as well as with the dual ErbB1/ErbB2 inhibitor
lapatinib, to assess the effectiveness of simultaneous targeting of ErbB1 and ErbB2 signaling over single inhibitor treatments in suppressing
cholangiocarcinoma cell growth in vitro and the therapeutic efficacy of
lapatinib in vivo. Our in vitro studies were carried out using rat (BDEneu and C611B) and human (HuCCT1 and TFK1)
cholangiocarcinoma cell lines. 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 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 effect in inhibiting liver
tumor growth in rats with more advanced
tumors.
CONCLUSION: