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Overexpression of PI3K p110α contributes to acquired resistance to MET inhibitor, in MET-amplified SNU-5 gastric xenografts

Authors Ji F, Liu X, Wu Y, Fang X, Huang G

Received 28 May 2015

Accepted for publication 29 June 2015

Published 19 October 2015 Volume 2015:9 Pages 5697—5704

DOI https://doi.org/10.2147/DDDT.S89410

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Prof. Dr. Wei Duan


Fujian Ji,1 Xuanwen Liu,2 Yuanyu Wu,1 Xuedong Fang,1 Guomin Huang1

1Department of General Surgery, The China–Japan Union Hospital of Jilin University, Changchun, 2Department of General Surgery, Jilin Central Hospital, Jilin, People’s Republic of China

Abstract: Gastric cancer is one of the most virulent malignant diseases and is the second leading cause of cancer mortality in the world. The receptor tyrosine kinase MET is constitutively activated in many gastric cancers and its expression is strictly required for survival of some gastric cancer cells. Targeting gastric cancers with amplified or abnormally activated MET may have therapeutic benefit based on nonclinical and emerging clinical findings. However, one of the major problems of therapies targeting tyrosine kinases is that many tumors are not responsive to treatment or eventually develop resistance to the drugs. This study aims to understand the mechanisms of MET resistance in gastric SNU-5 xenografts which developed resistance to PHA665752, a MET inhibitor, through long-period tyrosine kinase inhibitor exposure. In the current study, we found that PI3K p110α is overexpressed in PHA665752-resistant SNU-5 xenografts. These findings showed that high PI3K p110α expression contributes to tyrosine kinase inhibitor resistance. In addition, we reported the development of a carcinogen-induced gastric cancer model that recapitulates PI3K p110α expression in human disease, which will serve as a useful model to study PI3K p110α’s biology and its effectiveness as a novel biomarker and a molecular target for gastric cancer. Ultimately, PI3K p110α represents a novel target for gastric cancer.

Keywords: MET, SNU-5, gastric cancer, PI3K p110α, tyrosine kinase inhibitor resistance

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