Abstract 1732: Biomarker-driven inhibition of MET and EGFR pathways in hepatocellular and cholangiocarcinoma models with increased efficacy in a sorafenib-tolerant model
Authors: Tijeras-Raballand Annemilai , Serova Maria , Martinet Matthieu , Bièche Ivan , Paradis Valérie , Raymond Eric , Faivre Sandrine , Gramont Armand de 
Published: May 2015

Introduction: c-MET and EGFR pathways are often deregulated in human cancer progression including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CK), in which high levels of c-MET and EGFR have been correlated with poor prognosis. Moreover, MET and EGFR has been involved in sorafenib and platinum resistance. Our study was aimed at characterizing MET and EGFR expression in various HCC and CK models and to evaluate their inhibition on cell properties in terms of cell signaling, viability, and invasion.

Material and Methods: SU11274 and lapatinib are specific inhibitors of activated MET and EGFR/HER2 respectively. Antiproliferative effects were evaluated in the HCC cell lines, SK-HEP1 and its sorafenib-tolerant counterpart, SK-Sora as well as in the cholangiocarcinoma cell lines, Mz-chA-1, Mz-chA-2, OZ, HuCCT-1 and SK-CH using MTT assay. Protein levels were assessed by Western blot. Cell motility was investigated by wound-healing and matrigel invasion assays.

Results: Expression levels of MET and EGFR defined two subgroups of cells. SK-Sora, Mz-ch-A1, Mz-ch-A2 and HuCCT-1 expressed high levels of MET but low levels of EGFR (high-MET/low-EGFR cell lines); whereas SK-HEP1, OZ and SK-CH were characterized by low MET expression and high EGFR levels (low-MET/high-EGFR cell lines). These subgroups displayed differential sensitivity towards MET and EGFR inhibitors. Whereas 5µM SU11274 induced 62-85% growth inhibition in the group of high-MET/low-EGFR cells, low-MET/high-EGFR cells displayed 0-48 % growth inhibition. By contrast, low-MET/high-EGFR cells were much more sensitive to lapatinib than high-MET/low-EGFR cells with a mean growth inhibition at 20µM of 70% and 35%, respectively. As well, HGF-dependent invasion was more potently inhibited in high-MET/low EGFR than in low-MET/high-EGFR cells. Cells sensitivity to receptor inhibition could be explained by the intrinsic inducibility of MET and EGFR pathways. HGF-induced MET activation was associated with differential patterns of p-MET, p-GAB1, p-ERK1/2, and p-AKT between the two cell groups. This increased inducibility of high-MET/low-EGFR cells was translated into increased sensitivity to SU11274 inhibition compared to low-MET/high-EGFR cells. Differential effects of lapatinib on cell signaling and invasion will be detailed.

Conclusion: MET and EGFR expression profiles defined two subgroups of HCC and CK cell lines with differential inhibition sensitivity towards MET and EGFR inhibitors. To maximize the inhibition potential of these molecules, our results suggest that high-MET/low EGFR might be the candidate tumor types to evaluate MET inhibitors, whereas low-MET/high-EGFR tumors may be preferentially tested for EGFR pathway inhibition. Moreover, these results suggest that MET could be an attractive target in sorafenib resistant HCC patients.

Citation Format: Annemilai Tijeras-Raballand, Maria Serova, Matthieu Martinet, Ivan Bièche, Valérie Paradis, Eric Raymond, Sandrine Faivre, Armand de Gramont. Biomarker-driven inhibition of MET and EGFR pathways in hepatocellular and cholangiocarcinoma models with increased efficacy in a sorafenib-tolerant model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1732. doi:10.1158/1538-7445.AM2014-1732