title: Overexpression ofFGFR2contributes to inherent resistance to MET inhibitors inMET-amplified patient-derived gastric cancer xenografts.
abstract: Gastric cancer is one of the most malignant diseases and one of the leading causes of cancer-associated mortality worldwide. Although advances have been made in surgical techniques, perioperative management and the combined use of surgery with chemotherapy and/or radiotherapy, patients with advanced stage gastric cancer continue to face poor outcomes. Furthermore, it was reported thatMETgene amplification and overexpression predicted the sensitivity to MET inhibitors in gastric cancer. However, the identification of drug-resistant tumors has encouraged the pre-emptive elucidation of the possible mechanisms of clinical resistance. The current study assessed a number of patient-derived gastric cancer models withMETamplification and overexpression, including CNGAS028. The tumor tissues were subjected to microarray analysis (using single nucleotide polymorphism 6.0 and human genome U133 arrays) followed by western blotting. The results demonstrated that CNGAS028 xenograft tumors did not respond to treatment with a selective MET inhibitor. Additional analysis indicated thatFGFR2overexpression contributed to the resistance to MET inhibitors. Furthermore, treatment with a combination of fibroblast growth factor receptor 2 and MET inhibitors inhibited the growth of CNGAS028 xenograft tumorsin vivo. In conclusion, the current results aid in understanding the mechanism of inherent resistance to selective MET inhibitors as well as provide important information for patient selection and clinical treatment strategies.
authors.affiliation: Department of Gastrointestinal Surgery, Shandong Tumor Hospital, Jinan, Shandong 250117, P.R. China.
authors.forename: Kai
authors.initials: K
authors.lastname: Liu
authors.affiliation: Department of Gastrointestinal Surgery, Shandong Tumor Hospital, Jinan, Shandong 250117, P.R. China.
authors.forename: Xilin
authors.initials: X
authors.lastname: Song
authors.affiliation: Intensive Care Unit, Jinan Central Hospital, Jinan, Shandong 250013, P.R. China.
authors.forename: Meirong
authors.initials: M
authors.lastname: Zhu
authors.affiliation: Department of Gastrointestinal Surgery, Shandong Tumor Hospital, Jinan, Shandong 250117, P.R. China.
authors.forename: Heng
authors.initials: H
authors.lastname: Ma
keywords: MET; fibroblast growth factor receptor 2; gastric cancer; resistance