title: Identification of short-form RON as a novel intrinsic resistance mechanism for anti-MET therapy in MET-positive gastric cancer.
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.
authors.affiliation: Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Xiaoxiao
authors.initials: X
authors.lastname: Ge
authors.affiliation: Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Congqi
authors.initials: C
authors.lastname: Dai
authors.affiliation: Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Jinjia
authors.initials: J
authors.lastname: Chang
authors.affiliation: Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Xinyang
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Ruixuan
authors.initials: R
authors.lastname: Geng
authors.affiliation: Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Chenchen
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.|Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.|Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
authors.forename: Menghong
authors.initials: M
authors.lastname: Sun
authors.affiliation: Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Weijian
authors.initials: W
authors.lastname: Guo
authors.affiliation: Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Li
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000556:secondary; D008297:Male; D051379:Mice; D008819:Mice, Nude; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D012333:RNA, Messenger; D034741:RNA, Small Interfering; D019859:Proto-Oncogene Proteins c-met; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases
keywords: MET; RON; drug resistance; gastric cancer; targeted therapy