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Abstract
Clinical treatment options for human cholangiocarcinoma (CC) are limited. c-MET, a high-affinity receptor for hepatocyte growth factor (HGF), is deregulated in many cancers. Its role in cholangiocarcinogenesis remains unclear. In current study, 23 corresponding tumor- and non-tumor tissues, taken from patients with intrahepatic (iCC) and perihilar cholangiocarcinoma (pCC), who underwent liver resection, were analyzed. The relationship of clinicopathological features and c-MET, as well as c-jun N-terminal kinase (JNK) was evaluated. The anti-tumor effects of Tivantinib, a small-molecule inhibitor with potent activity against the c-MET kinase, was investigated in three human CC cell lines, namely HUCC-T1, TFK-1, and EGI-1. In comparison with the results obtained in non-tumor tissue samples, c-MET was overexpressed in 91.3 % of tumor tissues (p < 0.01). The JNK expression was higher in tumor tissue compared with the corresponding non-tumor tissue sample in 17.4% patients (p < 0.01). The inhibition of aberrant c-MET expression in human CC cell lines was achieved by blocking the phosphorylation of c-MET with Tivantinib. Notable losses in cell viability and colony-forming capability were detected (p < 0.01). Synergistic activation of the JNK/c-jun pathway was demonstrated after Tivantinib treatment. Knockdown of the JNK by siRNA or competitive binding of c-MET receptor by stimulation with HGF-antagonized anti-tumor effects of Tivantinib was observed. Our data suggest that inhibition of c-MET could be a possible alternative approach for the treatment of human CC, for which Tivantinib may an effective inhibitor. The synergistic activation of the JNK/c-jun pathway contributed to the elevated apoptosis in CC cells via treatment with Tivantinib.
Highlights
Untreated cholangiocarcinoma (CC) is one of most invasive malignancies with high mortality[1,2,3,4]
To validate the activation of c-MET signaling in CC carcinogenesis, the activation of c-MET expression was measured in 23 corresponding tumor- and non-tumor tissue samples taken from patients with iCC and perihilar cholangiocarcinoma (pCC)
Tivantinib failed two phase III studies involving secondline treatment of Met-high, advanced, hepatocellular carcinoma (METIV-HCC/JET-HCC), despite its success during phase II studies. The reasons for this might be multifactorial and discussion centers around trial design, inadequacies in the selection of patients according to tumor c-MET status, unclear definition for primary c-MET expression as biomarker for treatment, the inevitable upregulation of c-MET, which had been exposed during first-line treatments such as Sorafenib, and differences in implementation of Tivantinib during studies[22,38,39,40,41,42]
Summary
Untreated cholangiocarcinoma (CC) is one of most invasive malignancies with high mortality[1,2,3,4]. Most patients are diagnosed at an advanced stage, for which radical surgical resection is not feasible. The combination of Gemcitabine and Cisplatin is the only first-line palliative treatment for those patients and has limited benefits[5,6,7,8]. The pro-tumorigenic function of c-MET, a high-affinity receptor of the hepatocyte growth factor (HGF), has a critical role in many solid tumors, including human CCs9–16. Official journal of the Cell Death Differentiation Association. Wei et al Cell Death and Disease (2019)10:231 numerous clinicopathological factors. Tivantinib, a smallmolecule kinase inhibitor with potent activity against cMET, was investigated as an alternative therapeutic approach for CC in vitro
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