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RON (MST1R) is a novel prognostic marker and therapeutic target for gastroesophageal adenocarcinoma.

ABSTRACT: RON (MST1R) is one of two members of the MET receptor tyrosine kinase family, along with parent receptor MET. RON has a putative role in several cancers, but its expression and function is poorly characterized in gastroesophageal adenocarcinoma. A recognized functional role of MET tyrosine kinase in gastroesophageal cancer has led to early phase clinical trials using MET inhibitors, with unimpressive results. Therefore, the role of RON in gastroesophageal cancer, as well as its role in cooperative signaling with MET and as a mechanism of resistance to MET inhibition, was studied in gastroesophageal tissues and cell lines. By IHC, RON was highly over-expressed in 74% of gastroesophageal samples (n=94), and over-expression was prognostic of poor survival (p=0.008); RON and MET co-expression occurred in 43% of samples and was prognostic of worst survival (p=0.03). High MST1R gene copy number by quantitative polymerase chain reaction, and confirmed by fluorescence in situ hybridization and/or array comparative genomic hybridization, was seen in 35.5% (16/45) of cases. High MST1R gene copy number correlated with poor survival (p=0.01), and was associated with high MET and ERBB2 gene copy number. A novel somatic MST1R juxtamembrane mutation R1018G was found in 11% of samples. RON signaling was functional in cell lines, activating downstream effector STAT3, and resulted in increased viability over controls. RON and MET co-stimulation assays led to enhanced malignant phenotypes over stimulation of either receptor alone. Growth inhibition as evidenced by viability and apoptosis assays was optimal using novel blocking monoclonal antibodies to both RON and MET, versus either alone. SU11274, a classic MET small molecule tyrosine kinase inhibitor, blocked signaling of both receptors, and proved synergistic when combined with STAT3 inhibition (combination index < 1). These preclinical studies define RON as an important novel prognostic marker and therapeutic target for gastroesophageal cancer warranting further investigation.

SUBMITTER: Catenacci DV

PROVIDER: S-EPMC3149873 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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RON (MST1R) is a novel prognostic marker and therapeutic target for gastroesophageal adenocarcinoma.

Catenacci Daniel V T DV Cervantes Gustavo G Yala Soheil S Nelson Erik A EA El-Hashani Essam E Kanteti Rajani R El Dinali Mohamed M Hasina Rifat R Brägelmann Johannes J Seiwert Tanguy T Sanicola Michele M Henderson Les L Grushko Tatyana A TA Olopade Olufunmilayo O Karrison Theodore T Bang Yung-Jue YJ Kim Woo Ho WH Tretiakova Maria M Vokes Everett E Frank David A DA Kindler Hedy L HL Huet Heather H Salgia Ravi R

Cancer biology & therapy 20110701 1

RON (MST1R) is one of two members of the MET receptor tyrosine kinase family, along with parent receptor MET. RON has a putative role in several cancers, but its expression and function is poorly characterized in gastroesophageal adenocarcinoma. A recognized functional role of MET tyrosine kinase in gastroesophageal cancer has led to early phase clinical trials using MET inhibitors, with unimpressive results. Therefore, the role of RON in gastroesophageal cancer, as well as its role in cooperati ...[more]

PMID: 21543897

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Project description:PURPOSE:This study evaluates the prognostic significance of MST1R (RON) expression in breast cancer with respect to disease progression, long-term survival, subtype, and association with conventional prognostic factors. METHODS:The approach includes interrogation of survival and tumor staging with paired MST1R RNA expression from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. Protein expression evaluation was performed using immunohistochemistry (IHC) staining of MST1R on breast cancer tissue samples from the Cancer Diagnosis Program Breast Cancer Progression tissue microarray and locally obtained breast tumor tissue samples analyzed with paired survival, metastasis, and subtype. RESULTS:Data from TCGA (n?=?774) show poorer relapse-free survival (RFS) in patients with high MST1R expression (P?=?0.32) and no difference in MST1R expression based on tumor stage (P?=?0.77) or nodal status (P?=?0.94). Patients in the GEO-derived Kaplan-Meier Plotter microarray dataset demonstrate the association of MST1R and poorer overall survival (n?=?1402, P?=?0.018) and RFS in patients receiving chemotherapy (n?=?798, P?=?0.041). Patients with high MST1R expression display worse overall survival (P?=?0.01) and receiver operator characteristic (ROC) analysis demonstrate the predictive capacity of increased MST1R with early death (P?=?0.0017) in IHC-stained samples. Paired IHC-stained breast tumor samples from the primary versus metastatic site show MST1R expression is associated with metastatic progression (P?=?0.032), and ROC analysis supports the predictive capacity of MST1R in metastatic progression (P?=?0.031). No associations of MST1R with estrogen receptor (ER), progesterone receptor (PR), both ER and PR, HER2 positivity, or triple-negativity were found (P?=?0.386, P?=?0.766, P?=?0.746, P?=?0.457, P?=?0.947, respectively). CONCLUSIONS:MST1R expression has prognostic value in breast cancer with respect to survival and metastatic progression. MST1R expression is not associated with tumor stage, nodal status, or subtype.

Dataset Information

RON (MST1R) is a novel prognostic marker and therapeutic target for gastroesophageal adenocarcinoma.

Publications

RON (MST1R) is a novel prognostic marker and therapeutic target for gastroesophageal adenocarcinoma.

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