Abstract 27: Combination of paclitaxel and Sym015, a mixture of two monoclonal antibodies directed at MET receptor, to increase anti-tumor effects in gastric cancer
Authors: Hyun Jeong Kim, Sun Kyoung Kang, Ivan Horak, Michael Kragh, Woo Sun Kwon, Tae Soo Kim, Inhye Jeong, Sun Young Rha, Hyun Cheol Chung
Journal: Cancer Research (2017)

Abstract MET is a proto-oncogene that encodes a protein known as hepatocyte growth factor receptor (HGFR), involved in proliferative, survival and invasive/metastatic abilities of cancer cells. MET has received considerable attention as a potential target for cancer therapy, including gastric cancer (GC). MET amplification is present in 4-5% of GC patients, and associated with poor outcomes and significantly shorter median survival. Although intensive efforts have been directed toward the development of HGF-MET axis inhibitors, there are some issues for clinical translation; 1) proper biomarker to select patients, 2) proper chemotherapy combination partner and 3) proper line of treatment. Therefore, exploring drug to inhibit HGF-MET axis is essential. Among them, Sym015 (Copenhagen, Demark), a mixture of two monoclonal antibodies directed at MET receptor, is one of the leading agents in the pipeline. In this study, we had 49 GC cell lines including 27 Korean cancer patients. Those cells were analyzed by whole exome sequencing (WES) and RNA sequencing to understand biological and molecular characteristics. Also, expression levels of MET and MET-associated molecules were determined by western blot and HGF expression was evaluated by ELISA. Sensitivity of Sym015 was screened in 49 GC cell lines and combination with paclitaxel was performed in 6 MET amplification cell lines by CCK-8 assay. Combination index (CI) and dose reduction index (DRI) were evaluated by CalcuSyn software. Among 49 GC cell lines, we confirmed 6 cell lines with MET amplification including 2 novel Korean cancer patient cell lines (YCC-31 and YCC-34) and 17 (34.7 %) cell lines were sensitive to Sym015 with 20~68 % inhibition rate at 100 nM. And our data showed that Sym015 was related to MET amplification, c-Met/p-Met overexpression and exon 14 deletion, as we expected. Also, the 6 MET amplified cell lines (SNU5, SNU520, MKN45, YCC-31, YCC-34 and Hs746T) were all sensitive to Sym015 and down-regulate expression of c-Met/p-Met. Using MET amplified GC cell lines, we evaluated the efficacy and potential mechanism of Sym015 in combination with paclitaxel, which is the standard agent for second line treatment of metastatic GC. CI values determined at the ED50 indicated that 3 of 6 cell lines (MKN45, SNU520 and YCC-31) had synergistic effects (CI values &amp;lt; 0.7). When used in combination to treat 4 cell lines (MKN45, SNU520, YCC-31 and Hs-746T), the dose at ED50 of Sym015 could be reduced by 2.2-13.6 fold, based on DRI analysis. Also, the DRI for paclitaxel indicated that dose reductions up to 4.7-7.1 fold (MKN45 and SNU520) could be obtained. Our results indicate that Sym015 was sensitive to MET amplified cell lines and the Sym015 combined with paclitaxel therapy had synergistic effects in MET amplified GC. Citation Format: Hyun Jeong Kim, Sun Kyoung Kang, Ivan Horak, Michael Kragh, Woo Sun Kwon, Tae Soo Kim, Inhye Jeong, Sun Young Rha, Hyun Cheol Chung. Combination of paclitaxel and Sym015, a mixture of two monoclonal antibodies directed at MET receptor, to increase anti-tumor effects in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 27. doi:10.1158/1538-7445.AM2017-27