Abstract A188: MET inhibition by SU11274 impairs proliferation, motility, and invasion in hepatocellular and cholangiocarcinomas.

Background: Hepatocellular carcinomas (HCC) and cholangiocarcinomas (CK) are the most common primary tumors of the liver and are recognized among the most difficult tumors to treat. Signaling mediated by hepatocyte growth factor (HGF)/MET promotes multiple biological activities, including cell proliferation, motility, invasion, angiogenesis, and morphogenesis. Advanced HCC and CK are often displaying aberrant MET signaling and MET overexpression was observed in many tumors resistant to tyrosine kinase inhibitors (TKI). The aim of present study was to evaluate the effects of MET inhibition by SU11274 on HCC and CK cell proliferation and invasion. Materials and Methods: SU11274 is a pyrrole indolinone that specifically inhibits overexpressed and oncogenic MET activation at nanomolar concentrations. MET expression was assessed on human paraffin-embedded liver section by immunohistochemistry. Antiproliferative effects of SU11274, were evaluated in human HCC (SK-Hep1 and its sunitinib-tolerant counterpart SK-Suni) and CK (Mz-chA-1, Mz-chA-2, SK-ch) cell lines using a MTT assay. mRNA expression and protein levels were respectively assessed by qRT-PCR and Western blot. Cell mobility was investigated by wound-healing and matrigel invasion assays. Results: Higher MET protein expression was observed in human HCC and CK samples respect to normal tissues. MET-protein and -mRNA expression were detectable in all tested cell lines, Mz-ChA-1 and Mz-ChA-2 expressing higher MET levels. HGF-induced MET activation was associated with increase of p-METTyr1234/35, p-GAB1, p-ERK1/2, and p-AKTser473 in SK-CH, Mz-chA-2, SK-Hep1 and SK-Suni cells. We show that SU11274 inhibited HGF-induced downstream signaling by reducing p-METTyr1234/35, p-GAB1, p-AKT473 and p-ERK1/2 in HCC and CK cells at concentrations ranging from 0.5 to 2μM. However, antiproliferative effects were only observed for concentration above 2 μM (2,5 and 5 μM), In SK-Suni cells that are tolerant to high dose of sunitinib, proliferation was not inhibited even at the higher SU11274 dose (5μM). Interestingly, SU11274 potently decreased the spontaneous and HGF-dependent cell motility and invasion of Mz-chA-2 cells. Conclusion: In HCC and CK cells, inhibition of MET-signaling by SU11274 resulted in inhibition of cell proliferation, motility and invasion. HCC and CK may be interesting tumor types to evaluate novel MET inhibitors either as single agents and/or in combination with other targeted therapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A188.