Copyright ©2008 The WJG Press and Baishideng.
World J Gastroenterol. Dec 14, 2008; 14(46): 7033-7058
Published online Dec 14, 2008. doi: 10.3748/wjg.14.7033
Table 1 Rodent models of intrahepatic cholangiocarcinoma constitutively overexpressing ErbB2/Neu in cancerous epithelium
Tyrosine phosphorylationRef.
Development timeIncidence (%)Classificationc-erbB-2/neumRNAProtein
Furan rat model> 1 yr70-100Intestinal-type cholangiocarcinomaWild-type/non-amplifiedIncreasedIncreasedIncreased[63,64]
Thioacetamide rat model16-22 wk100Intestinal-type cholangiocarcinomaNANAIncreasedNA[65]
P53 deficiency/CCl4 mouse model≥ 16 wk40Ductal cholangiocarcinomaNANAIncreasedNA[66]
Rat BDEneu orthotopic cell transplantation model4 wk100Ductal cholangiocarcinomaMutatedIncreasedIncreasedIncreased[68,69]
Table 2 Selected anti-cancer agents targeting ErbB family receptors
AgentClass/TypeTargetRoute of administrationDevelopment stageRef.
Trastuzumab (Herceptin)Recombinant humanized mAbExtracellular domain of ErbB2Intravenous infusionApproved (ErbB2-positive breast cancer)[150-152]
Pertuzumab (Omnitarg, 2C4)Recombinant humanized mAbDimerization domain of ErbB2Intravenous infusionPhase II/III[151,153,154]
Cetuximab (Erbitux, C225)Recombinant human/mouse chimeric mAbExtracellular domain of EGFRIntravenous infusionApproved (EGFR-positive metastatic colorectal cancer and squamous cell carcinoma head and neck cancer)[151,155-157]
Panitumumab (ABX-EGF, Vectibix)Fully human mAbExtracellular domain of EGFRIntravenous infusionApproved (EGFR-positive metastatic colorectal cancer)[157-159]
Matuzumab (EMI-72000)Recombinant humanized mAbExtracellular domain of EGFRIntravenous infusionPhase I/II[157,159,160]
MDX-447Humanized bispecific mAbExtracellular domain of EGFR and high affinity IgG receptor CD64Intravenous infusionPhase I/II[157,161]
Gefitinib (Iressa)Anilinoquinazoline/Reversible TKIEGFR tyrosine kinaseOralLimited approval (NSCLC)[157,162-164]
Erlotinib (Tarceva)Anilinoquinazoline/Reversible TKIEGFR tyrosine kinaseOralApproved (NSCLC and pancreatic cancer)[153,155,157,165,166]
Lapatinib (Tykerb, GW572016)Thiazolylquinazoline/Reversible TKIEGFR and ErbB2 tyrosine kinasesOralApproved (ErbB2-positive advanced metastatic breast cancer)[157,166-169]
PKI-166Pyrrolopyrimidine/Reversible TKIEGFR and ErbB2 tyrosine kinasesOralPhase I[153,155,157,166,170]
BMS-599626Pyrrolotriazine/Reversible TKIEGFR and ErbB2 tyrosine kinasesOralPhase I[171,172]
EKB-569 (Pelitinib)Cyanoquinoline/Irreversible TKIEGFR tyrosine kinaseOralPhase I/II[157,166,173]
BIBW-2992Anilinoquinazoline/Irreversible TKIEGFR and ErbB2 tyrosine kinasesOralPhase I/II[168,174]
CI-1033 (Canertinib)Anilinoquinazoline/Irreversible TKIPan-ErbB tyrosine kinasesOralPhase I/II[153,157,164,168]
HKI-272Cyanoquinoline/Irreversible TKIPan-ErbB tyrosine kinasesOralPhase I/II[153,164,168,175]
Table 3 Preclinical biological effects of ErbB RTK inhibitors alone or combined with other target-based treatments for biliary tract cancer cells
AgentTargetExperimental conditionBiliary cancer cell line/tumorBiological effectsRef.
GefitinibEGFRCell cultureHAG-1 human gallbladder adenocarcinoma cell lineDose-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 radiationEGFRCell cultureHuCCT1 human intrahepatic cholangiocarcinoma cell line; TFK-1 human bile duct carcinoma cell lineGefitinib induced increase in radiosensitivity of HuCCT1 and TFK-1 cells[177]
Cetuximab + erlotinibEGFRCell culture and subcutaneous tumor xenografts in athymic nude miceHuCCT1 cell lineCombined 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-1040EGFR + MEK-Erk1/2Cell culture and subcutaneous tumor xenografts in athymic nude miceHuCCT1 cell lineDrug 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]
LapatinibEGFR/ErbB2Cell cultureRat C611B and human HuCCT1 cholangiocarcinoma cell linesLapatinib 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-AEE788EGFR/ErbB2 and VEGFR-2Cell culture and subcutaneous tumor xenografts in athymic nude miceEGI-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 linesNVP-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 + CelecoxibErbB2 +COX-2Cell cultureC611B rat intrahepatic cholangiocarcinoma cell lineEmodin 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 GW2974EGFRBK5.erbB2 transgenic mice constitutively expressing wild-type rat ErbB2Gallbladder adenocarcinomaBoth 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]
Table 4 Outcomes of ErbB-targeted therapies in patients with advanced biliary cancer
Assessable patientsTumorErbB statusErbB inhibitorTargetAdministrationResponseRef.
40Unresected or metastatic biliary tract cancers (gallbladder, intra- and extrahepatic bile duct)29/36 (81%) assessable tumor samples positive for EGFR expressionErlotinibEGFRSingle agentPR-3 patients; SD-17 patients; median time to disease-progression of 2.6 mo[185]
1Metastatic cholangiocarcinomaNegative EGFR expression in tumorCetuximabEGFRIn combination with 5'flurouracil, folic acid, and radiotherapyPR in intra-chemotherapeutic state[186]
1Unresected cholangiocarcinoma with peritoneal carcinomatosisPositive EGFR expression in tumorCetuximabEGFRIn combination with gemcitabinePR with 30% reduction in hepatic mass and disappearance of peritoneal carcinomatosis as shown by computed tomography[187]
9Unresected cholangiocarcinoma with disease progression after at least 3 cycles of gemcitabine-oxaliplatin9/9 (100%) tumor samples positive for EGFR expression, with all being negative for membranous ErbB2CetuximabEGFRIn combination with gemcitabine-oxaliplatinAfter 6 mo, CR-1 patient; PR-1 patient; SD-1 patient; progressive disease-6 patients; all patients relapsed, with a median time to disease progression of 4 mo[188]
17Unresected advanced biliary tract cancers (gallbladder, bile duct)Not reportedLapatinibEGFR/ErbB2Single agentNo observed responses; 5 patients with SD; cohort closed due to no noted lapatinib activity[189]
6 with biliary tract cancers out of a total of 34 with various types of solid tumorsAdvanced cholangiocarcinoma (5) or gallbladder cancer (1)Not investigatedLapatinibEGFR/ErbB2In combination with oxaliplatin/5-flurouracil/leucovorinPR-1 patient with cholangiocarcinoma and 1 patient with gallbladder cancer[190]
Table 5 Factors affecting ErbB-targeted therapies for intrahepatic cholangiocarcinoma and other biliary tract cancers
Patient selection and sampling size
Suboptimal drug dosing and/or scheduling
Tumor microenvironment and bioavailability
Intratumoral heterogeneity in receptor expression and activation
Receptor dynamic effects
Mutational effects
Different mechanisms of acquired resistance
Constitutive overexpression of ErbB family ligands
Co-activation of multiple receptor tyrosine kinases resulting in signaling redundancy and interplay
Lack of uniform biomarkers to effectively predict therapeutic response
Co-morbid disease and toxicity