title: 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.
authors.affiliation: University of Chicago, USA.
authors.forename: Daniel V T
authors.initials: DV
authors.lastname: Catenacci
authors.forename: Gustavo
authors.initials: G
authors.lastname: Cervantes
authors.forename: Soheil
authors.initials: S
authors.lastname: Yala
authors.forename: Erik A
authors.initials: EA
authors.lastname: Nelson
authors.forename: Essam
authors.initials: E
authors.lastname: El-Hashani
authors.forename: Rajani
authors.initials: R
authors.lastname: Kanteti
authors.forename: Mohamed
authors.initials: M
authors.lastname: El Dinali
authors.forename: Rifat
authors.initials: R
authors.lastname: Hasina
authors.forename: Johannes
authors.initials: J
authors.lastname: Brägelmann
authors.forename: Tanguy
authors.initials: T
authors.lastname: Seiwert
authors.forename: Michele
authors.initials: M
authors.lastname: Sanicola
authors.forename: Les
authors.initials: L
authors.lastname: Henderson
authors.forename: Tatyana A
authors.initials: TA
authors.lastname: Grushko
authors.forename: Olufunmilayo
authors.initials: O
authors.lastname: Olopade
authors.forename: Theodore
authors.initials: T
authors.lastname: Karrison
authors.forename: Yung-Jue
authors.initials: YJ
authors.lastname: Bang
authors.forename: Woo Ho
authors.initials: WH
authors.lastname: Kim
authors.forename: Maria
authors.initials: M
authors.lastname: Tretiakova
authors.forename: Everett
authors.initials: E
authors.lastname: Vokes
authors.forename: David A
authors.initials: DA
authors.lastname: Frank
authors.forename: Hedy L
authors.initials: HL
authors.lastname: Kindler
authors.forename: Heather
authors.initials: H
authors.lastname: Huet
authors.forename: Ravi
authors.initials: R
authors.lastname: Salgia
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D045744:Cell Line, Tumor; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D018628:Gene Dosage; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007211:Indoles / Q000494:pharmacology; D009154:Mutation; D010879:Piperazines / Q000494:pharmacology; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D017228:Hepatocyte Growth Factor; D007211:Indoles; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D019859:Proto-Oncogene Proteins c-met; D034741:RNA, Small Interfering; D020794:Receptor Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D017978:Receptors, Growth Factor; D050796:STAT3 Transcription Factor; D013449:Sulfonamides; C478479:((3Z)-N-(3-chlorophenyl)-3-((3,5-dimethyl-4-((4-methylpiperazin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-N-methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide); C066855:HGF protein, human; C494086:STAT3 protein, human; C082332:macrophage stimulating protein; C508053:ERBB2 protein, human; C491743:MET protein, human; C080835:RON protein