Abstract 3393: Targeting c-Met oncogene and the compensatory EGFR/ErbB3 pathways to eliminate c-Met activated hepatocellular carcinoma.

Abstract

Abstract Background: c-Met, a high-affinity receptor for Hepatocyte Growth Factor (HGF), plays a critical role in tumor growth, invasion, and metastasis. Hepatocellular carcinoma (HCC) patients with activated HGF/c-Met signals have a significantly worse prognosis. Although targeted therapies using c-Met tyrosine kinase inhibitors are currently in clinical trials for HCC, monotherapy using growth factor receptor tyrosine kinase inhibition in other cancers has demonstrated early success but the therapeutic effect is not durable due to the acquired resistance. Methods: We utilized the human MHCC97-H c-Met positive cell line to explore the compensatory survival mechanisms that are acquired after c-Met inhibition. MHCC97-H cells with stable c-Met knock-down (c-Met KD) were generated using a c-Met shRNA vector containing puromycin selection marker, and the scrambled shRNA transfected cells were served as a control. Gene expression profiling analyses were conducted, and protein expression assays were utilized to characterize MHCC97-H cells after blockade of c-Met oncogene. A high-throughput siRNA screen was performed to find the additional targets. The in vivo tumor growth assays were performed to evaluate the efficacy of either c-Met inhibition monotherapy or combined therapy with c-Met and EGFR inhibitors. Results: We have previously demonstrated that treatment of MHCC97-H cells with a c-Met inhibitor, PHA665752, results in stasis of tumor growth in vivo. c-Met KD MHCC97-H cells demonstrate slower growth kinetics, similar to c-Met inhibitor treated tumors. Using gene expression profiling analyses and siRNA screening against 873 kinases and phosphatases, we identified EGFR and ErbB3 as the compensatory survival factors that are up-regulated after c-Met inhibition, and those factors may represent the potential targets to further suppress c-Met+ HCC growth. In addition, we found that PI3K/Akt signal pathway serves as a negative feedback signal responsible for the ErbB3 up-regulation after c-Met inhibition. Furthermore, in vitro studies demonstrate that combination therapy with PHA665752 and Gefitinib (an EGFR inhibitor) significantly reduced cell viability and increased apoptosis compared with either PHA665752 or Gefitinib treatment alone. Moreover, we confirmed that combined therapy with c-Met and EGFR inhibitors resulted in a significant reduction of tumor volume compared with c-Met inhibition alone. Conclusion: c-Met inhibitor alone is not sufficient to eliminate c-Met+ HCC tumors. Inhibition of both c-Met and EGFR oncogenic pathways is necessary to further suppress c-Met+ HCC tumor growth. Citation Format: Wei Ding, Hien Dang, Steven Steinway, Hanning You. Targeting c-Met oncogene and the compensatory EGFR/ErbB3 pathways to eliminate c-Met activated hepatocellular carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3393. doi:10.1158/1538-7445.AM2013-3393