Abstract 3063: Predicting efficacy of c-Met targeting therapy in autocrine and paracrine tumor cell lines

Abstract

Abstract Tumor cells frequently harbor abnormalities in signaling pathways, leading to increased migration, invasion, survival, angiogenesis, and proliferation. C-Met is one such commonly aberrant pathway. Because of its effects on tumor cells, c-Met has been a target of interest for anti-metastatic therapies. Clinical trials of c-Met inhibition select patients based on total Met expression, or amplification of the Met gene. However, c-Met inhibitors target the activated pathway. We therefore predict that phospho-Met will be a better marker for patient sensitivity to, and hence selection for, c-Met inhibitor trials. C-Met is activated by the endogenous ligand Hepatocyte Growth Factor (HGF). In order to mimic the paracrine signaling during in vitro experiments, many studies add exogenous HGF at concentrations of 25-50 ng/mL. However, these concentrations may not be representative of in vivo conditions. HGF serum levels of healthy humans is 0.4 ng/mL. While HGF levels do rise in cancer patients, it is unusual to see serum levels higher than 1 ng/mL. Conditioned media from several cell lines (MDA-MB-231, PC-3, DU145, LNCaP, OS156, OS521, U87, U118, RKO, KHT, SCC7, and RIF) was collected to analyze for secretion of HGF in conditioned media. These cells were then examined for basal phosphorylation of Met. The cell lines that secreted HGF also had higher levels of phospho-Met in comparison to non-HGF-secreting cell lines. Importantly, levels of total Met did not predict for levels of phospho-Met. In migration and invasion assays, the HGF-secreting cell line KHT was found to be sensitive to the c-Met inhibitor BMS-777607.The non-HGF-secreting cell line DU145 only became sensitive to the inhibitor when high, non-physiologic exogenous levels of HGF (25-50 ng/mL) were added.These results suggest that autocrine activation of the c-Met pathway may be a factor in predicting sensitivity to c-Met inhibition. This may indicate the existence of a subset of patients most likely respond to c-Met inhibition therapy. Furthermore, consideration of exogenous HGF concentration should be considered when conducting preclinical trials of c-Met inhibitors, as addition of exogenous HGF may change the apparent efficacy of the inhibitor. Citation Format: Veronica S. Hughes, Dietmar W. Siemann. Predicting efficacy of c-Met targeting therapy in autocrine and paracrine tumor cell lines [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 3063. doi:10.1158/1538-7445.AM2017-3063