Abstract 810: Anti-tumor effects of Sym015 in HGF overexpressing gastric cancer cell lines
Authors: Kim Hyun Jeong , Kang Sun Kyoung , Kragh Michael , Horak Ivan D. , Kwon Woo Sun , Kim Tae Soo , Jeong Inhye , Ahn Joong Bae , Chung Hyun Cheol , Rha Sun Young 
Published: August 2018

MET, hepatocyte growth factor receptor (HGFR), has received considerable attention as a potential target for cancer therapy. MET and its ligand, HGF are associated with poor outcomes and significantly shorter overall survival in various cancer types including gastric cancer (GC). Although MET inhibitors have been shown to be sensitive to tumors with MET amplification, it is relatively rare that incidence is 4-5 % in GC and no MET inhibitor has succeeded in clinical trials so far. Therefore, development of better MET inhibitors and new biomarkers to identify proper patients to benefit from MET inhibitors is needed. We previously analyzed the sensitivity of a novel MET inhibitor, Sym015, a mixture of two human monoclonal antibodies directed at MET, according to MET/HGF status in 49 GC cell lines. Interestingly, two HGF overexpressing cell lines, IM95m and SNU484 were sensitive to 100 nM Sym015 with inhibition rate 52.3 and 23.4 %, respectively. HGF expression in lysate was 7,970 and 2,908 pg/ml and both cell lines had low levels of c-MET and p-MET. To evaluate the influence of HGF overexpression on the antitumor effect of Sym015, sensitivity was measured by CCK-8 assay and cell proliferation was determined by counting cells. Invasiveness was assessed through Transwell assay. Cell viability, invasiveness and related downstream molecules were assessed after HGF silencing by siRNA. In vivo, both cell lines were injected into BALB/c nude mice and Sym015 was applied (50mg/kg, 3qw) and tumor volume and weight were measured every other day. As a result, median inhibition rate of Sym015 in the two HGF overexpressing cell lines was 37.9 %, which was similar to the 44.9 % seen with MET amplified cell lines. The cell proliferation was delayed about 1.6 times and 1.2 times and also invasiveness was decreased by 12.9 and 29.5 % in IM95m and SNU484, respectively. After HGF silencing, inhibition rate at 100 nM Sym015 was significantly decreased (p=0.007) from 50.9 to 15.1 % due to AKT pathway activation in IM95m. There was no change in inhibition rate (from 12.2 to 14.8 %) and downstream pathway molecules in SNU484. Also, after silencing HGF expression, the inhibition effect of Sym015 on invasiveness was reduced from 29.8 % to no inhibition in SNU484 and there was no HGF silencing effect of Sym015 in invasiveness in IM95m. In vivo, xenograft models of IM95m and SNU484 both showed a significant reduction of 53.4 and 30.7 % in tumor volume at time of sacrifice, respectively (p&lt;0.0001). Especially Sym015 effectively inhibited the growth of tumor in IM95m than SNU484. Downstream molecular changes are under evaluation. Consequently, Sym015 was effective in HGF overexpressing cell lines and HGF overexpression induced Sym015 sensitivity was shown in IM95m and the inhibitory effect of invasiveness was shown in SNU484. We suggest that HGF overexpression influences the sensitivity of MET inhibitor and could be a potential predictive marker in GC.

Citation Format: Hyun Jeong Kim, Sun Kyoung Kang, Michael Kragh, Ivan D. Horak, Woo Sun Kwon, Tae Soo Kim, Inhye Jeong, Joong Bae Ahn, Hyun Cheol Chung, Sun Young Rha. Anti-tumor effects of Sym015 in HGF overexpressing gastric cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 810.