MerTK is a novel therapeutic target in gastric cancer.

Jun Ho Yi,Jeonghee Cho,Mineui Hong,Kyoung-Mee Kim,Ho Yeong Lim,In-Gu Do,Jeeyun Lee,Won Ki Kang,Se Hoon Park,Sujin Lee,Seung Tae Kim,Jiryeon Jang,Joon Oh Park,Young Suk Park

doi:10.18632/oncotarget.3750

Abstract

IntroductionThe role of MerTK has not been assessed in gastric cancer (GC). The aim of this study was to identify a subgroup of GC patients with MerTK tumor overexpression, and to evaluate MerTK as a potential therapeutic target in this disease.MethodsProtein and mRNA expression of MerTK were evaluated, and other various in vitro analyses including shRNA transfection, cell cycle anslysis, MTS assay and colony forming assay were carried out with GC cell lines and GC patient-derived cells (PDCs).ResultsshRNA-mediated knockdown of MerTK resulted in inhibition of cell growth, as well as increased cellular apoptosis in MerTK positive GC cells. Out of 192 GC patients, 16 (8.3%) patients showed strong protein expression and they had a significantly shorter overall survival compared to those with no MerTK expression. In 54 cases of GC PDCs, 4 cases (7.4%) showed mRNA overexpression, which was comparable to the protein expression rate. When we administered UNC1062, a novel MerTK-selective small molecular tyrosine kinase inhibitor, proliferation of MerTK overexpressing GC cells and PDCs were considerably inhibited.ConclusionMerTK may be involved in GC carcinogenesis, and it could be a potential novel therapeutic target in GC patients.

Highlights

The role of MerTK has not been assessed in gastric cancer (GC)
Results: small hairpin RNA (shRNA)-mediated knockdown of MerTK resulted in inhibition of cell growth, as well as increased cellular apoptosis in MerTK positive GC cells
MerTK may be involved in GC carcinogenesis, and it could be a potential novel therapeutic target in GC patients

Summary

Introduction

The role of MerTK has not been assessed in gastric cancer (GC). The aim of this study was to identify a subgroup of GC patients with MerTK tumor overexpression, and to evaluate MerTK as a potential therapeutic target in this disease. A number of receptor tyrosine kinases (RTKs) are implicated in the pathogenesis of cancer, and among them, aberrant activation of the TAM (Tyro-3, Axl, and MerTK) family of RTKs is known to be associated with pathogenesis of several malignancies, including melanoma [10, 11], leukemia [12,13,14], and glioma [15, 16]. They share structural similarity with a combination of 2 immunoglobin-like domains and dual fibronectin type III repeats in the extracellular region and a cytoplasmic kinase domain, and are involved in innate immune response [17], angiogenesis [18] and regulating nervous systems [19]. The detailed molecular mechanism underlying TAM RTKs-driven carcinogenesis remains unclear, previous in vivo and in vitro studies have suggested that activated anti-apoptotic pathways mediated by PI3K and MAPK via the TAM RTKs may play a crucial role in this mechanism

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