Increased HGF Expression Induces Resistance to c-MET Tyrosine Kinase Inhibitors in Gastric Cancer.

Abstract

Increased expression of hepatocyte growth factor (HGF) and MET proto-oncogene (c-MET) is associated with poor prognosis in various cancer types. Recently, it was reported that the expression of HGF induces resistance to tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor, human epidermal receptor receptor 2, and b-raf proto-oncogene. Here, we investigated the effects of HGF overexpression in gastric cancer cells in the absence or presence of c-MET TKIs. The effects of c-MET TKIs in gastric cancer cells with and without c-MET overexpression were determined in gastric cancer cell lines with various cell biology methods. Compared to the control, cells with induced expression of HGF showed increase in anchorage-independent colony formation (p<0.001). The c-MET TKIs inhibited HGF/c-MET downstream signaling, cell proliferation, migration and invasion, and triggered cell-cycle arrest in Hs746T cells. However, HGF-transfected cells were less affected. c-MET TKIs had inhibitory effects only on cells overexpressing c-MET. Furthermore, overexpression of HGF resulted in resistance to c-MET TKIs through an autocrine manner in gastric cancer cells.