Abstract LB-194: Therapeutic efficacy of ABN401, a highly potent and selective c-MET inhibitor, on the basis of diagnostic test for biomarkers in MET-amplified cancers

Abstract

Abstract The receptor tyrosine kinase c-MET regulates essential cellular processes in tissue remodeling and homeostasis, and mammalian development. Although c-MET is an important in normal physiology, the dysregulation of c-MET signaling has been strongly implicated in tumorigenic transformation, tumor growth, angiogenesis, invasiveness, and metastasis. The aberrant activation of c-MET, particularly in tumors with gene amplification and mutations, reported in a wide variety of cancers. In approximately 10% of gastric cancer, MET is amplified and is activated in the ligand-independent pathway. MET-amplified cancer cell lines are dependent on its signaling for survival and proliferation. That being so, c-MET is attractive target and a number of clinical trials are ongoing. However, some clinical trials were failed due to inappropriate patient selection criteria such as low cut-off. To select patients who respond to c-MET inhibitor, the selection criteria by using both IHC and FISH is necessary. In this study, we determined the efficacy of ABN401 based on histopathologic and genetic analysis using cell lines and patient-derived xenograft (PDX) models for gastric cancer and other c-MET related cancers as well. The cytotoxic effect of ABN401 was evaluated in six gastric cancer cell lines and one normal fibroblast cell as control by using cell viability assay. c-MET and its downstream signaling were assessed by western blot assay. In vivo anti-tumor therapeutic efficacy of ABN401 was evaluated in two gastric cancer cell xenograft models and eight PDX models. MET copy number, c-MET protein expression and genetic aberration were estimated by diagnostic test such as IHC and FISH, NGS, and array CGH in cell lines and PDX models. Our results revealed that ABN401 showed over 90% of cytotoxicity in five gastric cancer cell lines (SNU5, SNU620, SNU638, Hs746T, MKN45) and inhibited auto-phosphorylation of the c-MET as well as its downstream signal. Except for SNU638, the other four cell lines were MET copy number > 10, MET/CEP7 > 5, and c-MET expression (IHC 3+). Moreover, ABN401 significantly suppressed tumor growth in three of eight PDX models with MET copy number >5. MET/CEP7 > 5 and c-MET expression level (IHC 3+). However, ABN401 had no effect in gastric PDX model with MET copy number 5, MET/CEP7 ratio > 5, c-MET protein level IHC 2+ and esophagus PDX model with MET copy number 6, MET/CEP7 ratio = 2.2, IHC 1+. Both in vivo and in vitro experiment suggest that MET copy number and c-MET expression level affects effectiveness of c-MET inhibitor ABN401, which alert us the importance of cut-off. Based on this study, we conclude that it would be possible to make a conjecture in future clinical trials by establishing the characteristics of each sample and find the correlation with the efficacy of c-MET inhibitor. Citation Format: Jooseok Kim, Kyungsoo Jung, Kyungeui Park, Minji Seo, Yoonla Choi, Junyoung Choi, Sungyoul Hong, Youngkee Shin. Therapeutic efficacy of ABN401, a highly potent and selective c-MET inhibitor, on the basis of diagnostic test for biomarkers in MET-amplified cancers [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 LB-194.