Abstract 4935: Identification of GPR115 as a key G-protein coupled receptor as a key prognostic and therapeutic target in pancreatic ductal adenocarcinoma

Abstract

Abstract Purpose: Pancreatic ductal adenocarcinoma (PDAC) remains the fourth leading cause of cancer-related deaths in the United States, and the incidence of this disease continues to rise. Although recent advances in treatment modalities for this malignancy has somewhat improved patient outcomes in the recent years, the overall prognosis of patients with PDAC remains dismal. From a biological viewpoint, while the G-protein-coupled receptor (GPCRs) proteins play a multitude of important functions in tumor pathogenesis, their clinical significance if any in human cancers, especially PDAC, remains unclear. Herein we aimed to perform a comprehensive profiling of all GPCRs, in an attempt to identify the most critical protein(s) that have important biological and clinical significance in PDAC. Methods: This study included systematic analysis of 796 PDAC patients, which included data analysis from 331 patients from public datasets (TCGA, ICGC and GSE57495) and 465 patients from two, independent, clinical patient cohorts. Computational and bioinformatic analysis of genomewide expression profiling datasets led to the selection of candidate GPCR genes during the discovery and validation steps. The clinical significance of candidate genes were subsequently investigated in two in-house patient cohorts (training cohort: n = 321, validation cohort: n = 144) using qRT-PCR assays. The data were analyzed by performing appropriate statistical analyses to determine patient prognosis. Finally, using a series of functional studies, we confirmed the biological function of the candidate GPCRs in PDAC. Results: Analysis of all 33 GPCRs, led to the identification of GPR115, as the only significantly up-regulated candidate, with a prognostic significance in all three public datasets (P=0.02, 0.04 and 0.05, respectively). The patients with high-GPR115 expression exhibited significantly poorer postoperative prognosis for OS and RFS, in two, large, independent clinical cohorts (training cohort: P<0.01, P<0.01, validation cohort: P=0.01 and 0.02, respectively). More importantly, multivariate analysis indicated that high GPR115 expression was an independent prognostic factor in both cohorts (HR=1.45; P=0.01, HR=2.25; P<0.01). Using Cox regression, we established a risk-prediction model by incorporating GPR115 expression together with various clinicopathological factors, which was highly accurate in predicting 5-year long-term survival following surgery in PDAC patients. In addition, siRNA-mediated gene silencing of GPR115 significantly inhibited the cell proliferation and migration in human PDAC cells. Conclusion: We for the first time have identified GPR115 as a key GPCR with important prognostic significance, as well as functional role in tumor progression; providing a rationale that this may be a potential target for therapeutic targeting in patients with PDAC. Citation Format: Satoshi Nishiwada, Tadanobu Shimura, Kensuke Yamamura, Fuminori Sonohara, Takahiro Akahori, Kota Nakamura, Naoya Ikeda, Yasuhiro Kodera, Masayuki Sho, Ajay Goel. Identification of GPR115 as a key G-protein coupled receptor as a key prognostic and therapeutic target in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4935.