Preclinical assessment of simultaneous targeting of epidermal growth factor receptor (ErbB1) and ErbB2 as a strategy for cholangiocarcinoma therapy.
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.


CONCLUSIONS
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.
Zhang
Zichen
Z
Division of Cellular and Molecular Pathogenesis, Department of Pathology, Virginia Commonwealth University School of Medicine, Medical College of Virginia Campus, Richmond, VA, USA.
Oyesanya
Regina A
RA
Campbell
Deanna J W
DJ
Almenara
Jorge A
JA
Dewitt
Jennifer L
JL
Sirica
Alphonse E
AE
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001650:Bile Duct Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001653:Bile Ducts, Intrahepatic; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020032:Tyrphostins / Q000494:pharmacology / Q000627:therapeutic use
D000970:Antineoplastic Agents; D066246:ErbB Receptors; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D020032:Tyrphostins; C108081:AG 1517; C081020:AG-879; C508053:ERBB2 protein, human; C483804:Erbb2 protein, rat