HRH1: A Novel GPCR Drug Target in Pancreatic Cancer

Abstract

Patients with pancreatic cancer, in particular pancreatic ductal adenocarcinoma (PDAC), have a ~6% chance of surviving 5 years after diagnosis. Approved drugs only add weeks or months to patient lifespan. PDAC is difficult to treat, in part because the tumor often has poor vascularization and dense extracellular matrix, which yield a hypoxic tumor microenvironment. Finding new drugs for PDAC is thus an unmet medical need. The G protein‐coupled receptor (GPCR) superfamily is the most frequently targeted class of proteins for FDA‐approved drugs. We hypothesized that one or more GPCR may be a novel therapeutic target for PDAC.Bioinformatic analysis of PDAC tumors in TCGA [The Cancer Genome Atlas] revealed prominent (~32‐fold) overexpression of H1 histamine receptor (HRH1) compared to normal pancreatic tissue [GTex database]. KRAS and p53 mutations occur, respectively, in ~70% and ~60% of PDAC tumors whereas increased HRH1 expression of HRH1 in 100% of tumor samples in TCGA. HRH1 is an attractive target for repurposing since many FDA approved antagonists are directed at this receptor. We thus sought to validate HRH1 expression in PDAC cells.Using qPCR, we found high HRH1 expression and low expression of HRH2‐4 in BxPC, AsPC‐1, and CAPAN‐2 (PDAC) cell lines and normal pancreatic ductal epithelial cells. Addition of histamine increased Ca++ in ASPC‐1 and CAPAN‐2 cells; this increase in Ca++ was blocked by multiple FDA‐approved HRH1 antihistamines. Histamine increased PDAC cell proliferation in cells grown in hypoxia but not normoxia. High expression of HRH1 in PDAC cells may thus confer a growth advantage for PDAC cells in hypoxic conditions. These preliminary data suggest that FDA‐approved HRH1 antihistamines are candidates for repurposing as novel therapeutics for the treatment of pancreatic cancer.Support or Funding InformationSupported by HHMI and an ASPET David Lehr AwardThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.