Abstract LB-105: Therapeutic efficacy of ABN401, highly selective c-MET inhibitor, in NSCLC with MET-amplified AND/OR EGFR mutation

Abstract

Abstract c-MET, also known as a hepatocyte growth factor receptor encoded by the MET gene, plays role in normal physiology by regulating cellular physiology. In cancer, MET alterations containing gene amplification, mutation, overexpression have been strongly implicated in tumorigenic transformation, tumor growth, angiogenesis, invasion, and metastasis. These MET alterations are reported in a wide variety of cancers such as lung, gastric, colon, liver, and head and neck. Especially in NSCLC, MET amplification and mutations including exon 14 deletion are observed in 4% of patients. Also, in NSCLC, EGFR mutation is observed in about 15~35% of patients. Among those 15-35% of patients, approximately 5-11% of NSCLC patients, who were treated by EGFR TKi, experience acquire resistance mechanism induced by c-MET. Also, EGFR amplification and overexpression are acquired resistance mechanism for MET. The alterations and cross-reactivity between c-MET and EGFR induce cancer by bypassing mechanisms for each other. c-MET, which acts as a resistance mechanism after EGFR TKi treatment, makes c-MET as an attractive target for cancer therapy. In this study, we determined the efficacy of ABN401 and other tyrosine kinase targeting inhibitor by combination treatment based on genetic analysis using cell lines and PDX models for NSCLC. The cytotoxic effect of ABN401 and synergism was evaluated in five NSCLC cell lines. c-MET and its downstream signaling were also assessed. In vivo anti-tumor therapeutic efficacy of ABN401 was evaluated in one NSCLC cancer cell xenograft model and 4 PDX models. MET copy number, c-MET protein expression, and genetic aberration were also determined. Our results revealed that ABN401 shows over 60-90% cytotoxicity in five NSCLC cell lines (H596, H1993, EBC-1, H820, HCC827) between 10 nM to 10 uM and inhibits auto-phosphorylation of c-MET as well as its downstream signalling. H1993, H596, and EBC-1 showed cytotoxicity effect on several nM of single treatment of ABN401. Other cell lines which harbor EGFR mutations exhibited lower cytotoxicity effect single treatment of ABN401. Combination treatment of ABN401 and EGFR TKi showed about 80% of cytotoxic effect. The CI index, which is an indicator for synergism, appeared less than 1 in certain concentrations of combination therapy. In in vivo, single treatment of ABN401 showed tumor growth suppression on xenograft model with MET amplification and PDX model with MET amplification and Ex14del. PDX model with MET and EGFR amplification regardless of presence of EGFRm L858R, did not show tumor growth suppression by single treatment of ABN401. However, significant tumor growth suppression was observed when treated with both ABN401 and EGFRm TKi. Both in vivo and in vitro results suggest that single treatment of ABN401 has efficacious effects when MET is highly amplified regardless of MET Ex14del’s presence. Combination treatment of ABN401 and EGFRm TKi showed efficacious effect on both MET and EGFR amplification regardless of the presence of EGFR mutation. Based on this study, we concluded that ABN401 can be a potential drug candidate for NSCLC patients who has METamplification and/or Ex14del as a single agent as well as combination treatment for patients who show resistance to EGFR inhibitors and exhibit MET amplification. Citation Format: Joo Seok Kim, Kyeung Eui Park, Yeong Mun Kim, Kevin Sha, Min Ji Seo, Sungyoul Hong, Jun Young Choi, Young Kee Shin. Therapeutic efficacy of ABN401, highly selective c-MET inhibitor, in NSCLC with MET-amplified AND/OR EGFR mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-105.