Aberrant RON and MET Co-overexpression as Novel Prognostic Biomarkers of Shortened Patient Survival and Therapeutic Targets of Tyrosine Kinase Inhibitors in Pancreatic Cancer

Abstract

RON (recepteur d'origine nantais) and MET (hepatocyte growth factor receptor) are tyrosine kinase receptors. Various cancers have aberrant RON and MET expression and activation, which contribute to cancer cell proliferation, invasiveness, and metastasis. Here, we explored RON and MET expression in pancreatic cancer and their relationship with overall survival (OS) time, and evaluated their significance as therapeutic targets of tyrosine kinase inhibitors in pancreatic cancer. We enrolled 227 patients with pancreatic cancer in the study. RON and MET expression was analyzed by immunohistochemical staining. Four human pancreatic cancer cell lines expressing variable levels of RON or MET and four MET superfamily inhibitors (BMS777607, PHA665752, INCB28060, Tivantinib) were used. The effect of the four tyrosine kinase inhibitors on cell viability, migration, and apoptosis were determined using cell viability, scratch wound healing, and Caspase-Glo 3/7 assays. Cellular signaling was analyzed by immunoprecipitation and western blotting. The therapeutic efficacy of the tyrosine kinase inhibitors was determined with mouse xenograft pancreatic cancer models in vivo. There was wide aberrant RON and MET expression in the cancer tissues. In 227 pancreatic cancer samples, 33% had RON overexpression, 41% had MET overexpression, and 15.4% had RON and MET co-overexpression. RON and MET expression were highly correlated. RON and MET expression levels were significantly related to OS. Patients with RON and MET co-overexpression had poorer OS. BMS777607 and PHA665752 inhibited pancreatic cancer cell viability and migration, and promoted apoptosis by inhibiting RON and MET phosphorylation and further inhibiting the downstream signaling pathways in vitro. They also inhibited tumor growth and further inhibited phosphorylated (phosphor)-RON and phospho-MET expression in the mouse xenograft models in vivo effectively. INCB28060, which inhibits the MET signaling pathway alone, was not effective. RON and MET can be important indicators of prognosis in pancreatic cancer. Tyrosine kinase inhibitors targeting RON and MET in pancreatic cancer are a novel and potential approach for pancreatic cancer therapy.

Integrated transcriptome meta-analysis of pancreatic ductal adenocarcinoma and matched adjacent pancreatic tissues

“…Notably, violin plots of gene expression by pathological stages based on the TCGA PAAD data showed that twenty-one of the identified prognostic genes (ITGB6, LAMC2, KRT7, SERPINB5, IGF2BP3, IL1RN, MPZL2, SFTA2, MET, LAMA3, ARNTL2, SLC2A1, LAMB3, COL17A1, EPSTI1, IL1RAP, AK4, ANXA2, S100A16, KRT19, and GPRC5A) also significantly correlated with pathological stages of the disease, indicating that these genes may play crucial roles in the tumorigenesis of PDAC. As expected, some of these identified genes have been reported to be associated with poor overall survival of patients with pancreatic cancer ( Cheng et al, 2019 ; Hu et al, 2019 ; Jahny et al, 2017 ; Pei, Yin & Liu, 2018 ; Reader et al, 2019 ; Schaeffer et al, 2010 ; Takahashi et al, 2019 ; Wu et al, 2019 ; Yao et al, 2016 ; Zhang et al, 2019 ). However, the functional and clinicopathological significance of IL1RN, MPZL2, SFTA2, EPSTI1, IL1RAP, AK4 and S100A16 in PDAC have not been reported.…”

Comprehensive analysis of prognostic immune‑related genes associated with the tumor microenvironment of pancreatic ductal adenocarcinoma

“…Activation of several intracellular signaling pathways that is mediated by MET has led to the emergence of diverse cellular hallmarks of cancer, including cell proliferation, survival, invasion, migration, metastasis and inhibition of apoptosis (50)(51)(52). MET may be involved in the malignant process of pancreatic cancer, and can serve as a biomarker for assessing the prognosis of patients with pancreatic cancer (53). IL1R2, as an endogenous inhibitor, can be highly expressed in the follicular helper T cells of mice, and the specific marker molecules, such as IL1R2, on the surface of tumor infiltrating Treg cells in colorectal cancer and non-small cell lung cancer have also been demonstrated to be upregulated (54,55).…”

RON in hepatobiliary and pancreatic cancers: Pathogenesis and potential therapeutic targets

“…Among human pancreatic tissue samples, RON expression was detected in 83% of metastatic lesions, 79% of primary lesions, and 93% of high-grade PanIN using immunohistochemistry, with low expression being detected in low-grade PanIN and normal ducts (18% and 6%, respectively), suggesting that RON might function in pancreatic carcinogenesis and metastatic progression[ 22 ]. Moreover, RON expression levels were significantly related to overall survival in patients with pancreatic cancer, indicating that RON could be an important indicator of prognosis in pancreatic cancer[ 75 ]. Conflicting results between RON expression and pancreatic cancer prognosis were found in an early study[ 76 ], thus more research is needed to determine the utility of RON as a prognostic biomarker in patients with pancreatic cancer.…”