Abstract
Despite the promising results from initial studies, there are significant limitations in the application of MET-targeted therapy in gastric cancer. Intrinsic resistance is one of the major obstacles. The aim of this study is to identify the responsible receptor tyrosine kinases (RTKs) that determine the unresponsiveness of MET inhibitor in MET-positive gastric cancer. through an RNA-interference-based functional screen targeting most human RTKs, we identified that activation of the fibroblast growth factor receptor 2 (FGFR2) and recepteur d'origine nantais (RON) pathways attenuated MET inhibitor-induced suppression of cell proliferation and migration. Notably, in the two forms of RON pathway activation, only upregulation of short-form RON (sf-RON), but not stimulation of full length RON with macrophage stimulating protein, conferred MET inhibitor resistance in vitro and in vivo. Furthermore, the profile of the gastric cancer samples observed that sf-RON was frequently upregulated in MET-positive gastric cancer. Our findings indicate that activation of the sf-RON signaling pathway represents a novel mechanism underlying MET inhibitor unresponsiveness. A combination strategy with drugs targeting both RON and MET pathways is believed to improve the efficacy of MET-targeted therapy.
Highlights
MET, as a member of receptor tyrosine kinase (RTK) family, plays a causal role in tumor cell survival, growth, angiogenesis and metastasis [1]
SiRNA screening identifies RTKs influencing the sensitivity of gastric cancers (GCs) cells to PF
Our results indicated that MET+ MKN-45 cells were much more responsive to PF than the other METGC cell lines, with an IC50 of 0.018 μM (Supplementary Figure S1A and S1B)
Summary
MET, as a member of receptor tyrosine kinase (RTK) family, plays a causal role in tumor cell survival, growth, angiogenesis and metastasis [1]. Monoclonal antibodies and small-molecule tyrosine kinase inhibitors targeting the HGF/SF-MET pathway have been evaluated in preclinical experiments and clinical trials [9]. A double-blind and randomized phase 2 clinical trial showed that the addition of rilotumumab, a fully human monoclonal antibody of HGF, to chemotherapy improved the prognosis in patients with GC or esophagogastric junction cancer, especially in METpositive (MET+) subgroup. Clinical trials studying the efficacy of MET-targeted tyrosine kinase inhibitors (TKIs) as monotherapy in patients with www.impactjournals.com/oncotarget metastatic gastric adenocarcinoma only showed minimal efficacy, even in MET-amplified subgroup [11, 12]. Limited response rate and minimal efficacy suggested that a proportion of patients with MET+ stomach tumors may be insensitive to MET targeted therapy. Intrinsic resistance to MET inhibitors emerges as a major limitation in the application of MET-targeted therapy in gastric cancer
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