Oncotarget

Research Papers:

Identification of short-form RON as a novel intrinsic resistance mechanism for anti-MET therapy in MET-positive gastric cancer

Zheng Wu, Zhe Zhang, Xiaoxiao Ge, Ying Lin, Congqi Dai, Jinjia Chang, Xinyang Liu, Ruixuan Geng, Chenchen Wang, Huan Chen, Menghong Sun, Weijian Guo and Jin Li _

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Oncotarget. 2015; 6:40519-40534. https://doi.org/10.18632/oncotarget.5816

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Abstract

Zheng Wu1,2,*, Zhe Zhang1,2,*, Xiaoxiao Ge1,2, Ying Lin1,2, Congqi Dai1,2, Jinjia Chang1,2, Xinyang Liu1,2, Ruixuan Geng1,2, Chenchen Wang1,2, Huan Chen2,3, Menghong Sun2,3, Weijian Guo1,2, Jin Li1,2

1Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China

2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China

3Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China

*These authors have contributed equally to this work

Correspondence to:

Jin Li, e-mail: fudanlijin@163.com

Keywords: drug resistance, RON, MET, gastric cancer, targeted therapy

Received: April 20, 2015     Accepted: September 22, 2015     Published: October 26, 2015

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.


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