Abstract 3082: Biomarker-driven inhibition of MET and EGFR pathways in hepatocellular and cholangiocarcinoma models
Authors: Tijeras-Raballand Annemilai , Serova Maria , Martinet Matthieu , Colnot Nathalie , Albuquerque Miguel , Paradis Valérie , Raymond Eric , Faivre Sandrine , de Gramont Armand 
Published: July 2016

Introduction: In hepatocellular carcinoma (HCC) and cholangiocarcinoma (CK), high levels of c-MET and EGFR have been correlated with poor prognosis. Moreover, MET and EGFR has been involved in drug resistance. Our study was aimed at evaluating MET and EGFR inhibition on cell viability, invasion, MET and EGFR signaling as well as on sorafenib sensitivity.

Material and Methods: SU11274 and lapatinib are specific inhibitors of activated MET and EGFR/HER2 respectively. Antiproliferative effects were evaluated in 12 HCC and CK cell lines using MTT assay. Protein levels were assessed by Western blot. Cell motility was investigated by wound-healing and matrigel invasion assays. Ex vivo experiments testing SU11274 were performed on surgical specimens from HCC patients that were cut into 300μM-thick slices and grown in specific media for 48h. Tumor samples were analyzed by IF or IHC.

Results: Expression levels of MET and EGFR defined two subgroups of cells classified as high-MET/low-EGFR or low-MET/high-EGFR cell lines. These subgroups displayed differential sensitivity towards MET and EGFR inhibitors. High-MET/low-EGFR cells displayed high sensitivity to SU11274 (GI50 = 1,6-3,7μM) but not lapatinib (GI50&gt;20μM), whereas low-MET/high-EGFR cells were more sensitive to lapatinib (GI50 = 4,8-10,2μM) than SU11274 (GI50&gt;20μM). HGF-dependent invasion was more potently inhibited by SU11274 in high-MET/low EGFR than in low-MET/high-EGFR cells. Cells sensitivity to receptor inhibition could be explained by intrinsic cell responsiveness to MET and EGFR pathways activation. Increased responsiveness of high-MET/low-EGFR cells to HGF was translated into increased sensitivity to SU11274. Similarly, low-MET/high-EGFR cells were more responsive to EGFR and consequently more sensitive to lapatinib. Interestingly, SK-Hep1 cells resistant to sorafenib expressed increased level of MET and were subsequently more sensitive to MET inhibition. Ex vivo results will be detailed on the poster with c-MET, HE, Ki67, and caspase 3 expression.

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, Nathalie Colnot, Miguel Albuquerque, Valérie Paradis, Eric Raymond, Sandrine Faivre, Armand de Gramont. Biomarker-driven inhibition of MET and EGFR pathways in hepatocellular and cholangiocarcinoma models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3082.