Abstract 5391: Preclinical evaluation of AMG 337, a highly selective small molecule MET inhibitor, in hepatocellular carcinoma
Authors: Du Zhiqiang , Caenepeel Sean , Shen Yuqing , Rex Karen , Zhang Yanni , Tang En-Tzu , Wang Ouhong , Zhong Wenge , Zhou Hui , Huang Jacqueline , Huang Eric , Hu Liaoyuan , Coxon Angela , Zhang Mingqiang 
Published: August 2015

Abstract
Purpose: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Aberrant hepatocyte growth factor / MET signaling has been implicated in hepatocarcinogenesis, suggesting that MET may serve as an attractive therapeutic target in HCC. The purpose of this study was to investigate the anti-tumor activity in vitro and in vivo of AMG 337, a potent and highly selective small molecule MET kinase inhibitor, in preclinical models of HCC.
Experimental Design: The anti-proliferative activity of AMG 337 was evaluated across a panel of 40 HCC cell lines in a 72-hour viability assay. Daily oral administration of AMG 337 at doses of 3, 10 and 30 mg/kg was used to evaluate the in vivo anti-tumor activity of AMG 337 in two patient-derived mouse xenograft (PDX) models of HCC, LI0612 and LI1078. Effects on MET signaling were assessed by western blot analysis of downstream effector proteins including p-GAB1, p-AKT and p-ERK. MET protein levels and gene copy number for both PDX models and a subset of HCC cell lines were assessed by immunohistochemistry (IHC; Dako) and fluorescence in situ hybridization (FISH; Dako), respectively. High MET expression was defined as the presence of any tumor cells with membrane staining at 3+ intensity. MET amplification was defined as MET:CEN-7 ratio &gt;2.0 or MET SNP array log2 copy number &gt;2.5.
Results: AMG 337 displayed potent anti-proliferative activity in two of 40 HCC cell lines (MHCC97H and HCCLM3) (IC50 0.015 μM and 0.025 μM, respectively); both cell lines were amplified for MET (MET/CEN-7 &gt;2.0) and showed high MET expression (3+ IHC). AMG 337 potently inhibited p-MET in all cell lines with detectable levels of total MET. However, dose-dependent inhibition of p-GAB1, p-AKT and p-ERK was limited to those cell lines that were sensitive to AMG 337 in viability assays. AMG 337 significantly inhibited tumor growth at all doses tested (p &lt; 0.001) in the MET-amplified and MET-high expressing HCC PDX model LI0612. However, AMG 337 had no effect on tumor growth in the non-MET-amplified and MET-low expressing HCC PDX model LI1078. Analysis of The Cancer Genome Atlas (TCGA) data identified four of 164 (2.4%) HCC tumor samples with MET amplification (https://tcga-data.nci.nih.gov/tcga), representing a patient population with potential to derive clinical benefit from AMG 337.
Conclusions: These preclinical studies show that the efficacy of AMG 337 in HCC was highly associated with MET amplification. AMG 337 represents a promising, novel clinical therapeutic strategy for targeting HCC with a dependence on the MET pathway.
Citation Format: Zhiqiang Du, Sean Caenepeel, Yuqing Shen, Karen Rex, Yanni Zhang, En-Tzu Tang, Ouhong Wang, Wenge Zhong, Hui Zhou, Jacqueline Huang, Eric Huang, Liaoyuan Hu, Angela Coxon, Mingqiang Zhang. Preclinical evaluation of AMG 337, a highly selective small molecule MET inhibitor, in hepatocellular carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5391. doi:10.1158/1538-7445.AM2015-5391