Abstract
The prognosis of patients with biliary tract adenocarcinomas (BTA) is still poor due to lack of effective systemic treatment options. Knowledge of the molecular mechanisms involved in the pathogenesis of this disease is of importance for the development of new treatment strategies. We determined the expression of epidermal growth factor receptor (EGFR) and activated mammalian target of rapamycin (p-mTOR) in paraffin-embedded surgical specimens of BTA (n = 89) by immunohistochemistry. Overall survival was analyzed with Cox models adjusted for clinical and pathologic factors. Combined EGFR/p-mTOR expression was significantly associated with relapse-free survival [adjusted hazard ratio for relapse, 2.20; 95% confidence interval (95% CI), 1.45-3.33; P < 0.001] and overall survival (adjusted hazard ratio for death, 2.32; 95% CI, 1.50-3.58; P < 0.001) of the patients. The effect of the EGFR inhibitors erlotinib or cetuximab and the mTOR inhibitor rapamycin on growth and survival of five BTA cell lines was tested in short-term 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays and long-term colony formation assays. Simultaneous blockade of EGFR and mTOR in biliary tract cancer cell lines results in a synergistic inhibition of both phosphatidylinositol-3-kinase and mitogen-activated protein kinase pathways, leading to reduced cell growth and survival. These results suggest that combined targeted therapy with EGFR and mTOR inhibitors may potentially benefit patients with BTAs and should be further evaluated in clinical trials.
Highlights
Prognosis of patients with adenocarcinoma of the biliary tract (BTA) is still poor
epidermal growth factor receptor (EGFR) expression was significantly associated with intrahepatic cholangiocarcinoma compared with other anatomic locations (P < 0.001) and with G2 tumors (P = 0.05)
Several observations indicate that EGFRmediated signals and the PI3K-AKT-mammalian target of rapamycin (mTOR) signaling pathway could play a key role in the pathogenesis of this disease [22, 23]
Summary
Prognosis of patients with adenocarcinoma of the biliary tract (BTA) is still poor. Due to lack of characteristic early symptoms, a definitive diagnosis is often established at an advanced stage in the majority of the patients [1]. For patients with resectable BTA, surgery remains the only definitively curative therapy; even after complete resection, recurrence rates are high. In advanced BTA, systemic treatment is necessary but there are no effective systemic treatment options available at the moment. Knowledge of molecular pathways associated with the pathogenesis of BTAs may help to devise new treatment strategies to improve the clinical outcome of the patients. The epidermal growth factor receptor (EGFR, HER1), as well as the downstream pathway phosphatidylinositol-3kinase (PI3K)-protein kinase B (AKT)-mammalian target of rapamycin (mTOR) are in the focus of interest to develop novel targeted therapies [2, 3]
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