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  • At the therapeutic level the

    2019-09-17

    At the therapeutic level, the logical approach to address the cooperation between FGFR4 and EGFR was the combined inhibition of both receptors. To explore the potential efficacy and specificity of this approach, we tested the effect of FGFR and EGFR inhibitors in monotherapy or in combination in syngeneic models with FGFR4 overexpression in vitro and in vivo. We found that the combined inhibition showed superior and dramatic effects in terms of proliferation or tumor growth than when either inhibitor was used alone, especially in models with induced FGFR4 expression, thereby demonstrating the potential efficacy of this combined treatment in EGFR-activated, FGFR4-expressing tumors. These results suggest that dual EGFR/FGFR inhibition may serve as a potentially effective therapy for patients with high EGFR activation and FGFR4 expression.
    Conclusions
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    Acknowledgements
    Introduction Cholangiocarcinoma (CCA) is an unusual adenocarcinoma arising from biliary epithelial cells, anywhere along the intra- and extrahepatic biliary tree, excluding the ampulla of the Vater and the gall bladder. It is one of the most fatal primary liver malignant tumors and the most common malignant tumor of the biliary tract worldwide (Massarweh and El-Serag, 2017; Khan et al., 2012). According to the anatomical orientation, CCA could be divided into three classes: intrahepatic cholangiocarcinoma (ICC), hilar cholangiocarcinoma, and extrahepatic cholangiocarcinoma (ECC) (Tyson et al., 2014). Most CCA patients were diagnosed at advanced stages when they are often not eligible for surgical treatment. As a result, the 5-year survival rate of CCA is estimated to be 10% during past decades (Skipworth et al., 2011). The main treatment for CCA patients is surgical resection, while its recurrence and Spautin-1 rates remain very high (Nassour et al., 2018). Molecular biology of CCA pathogenesis may provide effective treatment strategies and improve patient outcomes (Kongpetch et al., 2015). Therefore, it is urgent to clarify the underling mechanism and search optional therapeutic targets. Neurotensin (NTS) is a 13 amino acid neuropeptide. It has been reported to be involved in the regulation of prolactin release and luteinizing hormone and has important associations with the dopaminergic system (Carraway and Leeman, 1973; Reinecke, 1985). NTS was first extracted from the bovine hypothalamus because it could cause visible vessel expansions in exposed cutaneous regions of anesthetized rats (Rosell et al., 1980). Intestinal mucosa endocrine cells release NTS into the portal vein after meals, especially those rich in fatty acids, and then, it is metabolized by the liver (Ferris et al., 1985). NTS has numerous biological effects, including the promotion of normal tissue growth and activity in tumors initiation and progression (Evers, 2006; Mustain et al., 2011). NTS actions are mediated by three subtypes of NTS receptors (NTSRs). These receptors include NTSR1 and NTSR2, which exhibit high and low affinity for NTS (Chalon et al., 1996). NTS and its receptors play important roles in the initiation and progression of a broad range of human tumors, comprising breast, prostate, lung, liver, and pancreas cancers (Dupouy et al., 2009; Souaze et al., 2006; Alifano et al., 2010; Wang et al., 2011; Allen et al., 1988). It has been reported that NTS affected the growth and metastasis of different tumor types due to the dysregulation of NTS and NTSRs during the early stage of tumor initiation. This implies that NTS and NTSRs may serve as pharmacological targets and markers of prognosis and diagnosis in numerous tumors (Dupouy et al., 2009; Alifano et al., 2010; Dupouy et al., 2014). However, the regulatory role of NTS in CCA remains unknown.
    Materials and methods
    Statistical analysis GraphPad Prism (GraphPad Software, Inc. La Jolla, USA) was used for all statistical analyses. Statistical analysis was conducted using either the t-test or the Bonferroni Multiple Comparisons Test: *p < 0.05. A p value below 0.05 was considered as statistically significant.