Pharmacologic activation of G protein-coupled estrogen receptor inhibits pancreatic ductal adenocarcinoma

Abstract

Female sex is associated with lower incidence and improved clinical outcomes for many cancer types, including pancreatic ductal adenocarcinoma (PDAC). Although the mechanisms responsible for this sex difference are unknown, recent data suggests nonclassical estrogen signaling through the G Protein-coupled Estrogen Receptor (GPER) is likely involved. Here we used murine syngeneic tumor models and human xenografts to test whether GPER signaling inhibits pancreatic ductal adenocarcinoma (PDAC). Activation of GPER with the specific, small molecule agonist G-1 inhibited PDAC proliferation, depleted c-Myc and programmed death ligand 1 (PD-L1), and increased tumor cell immunogenicity. Systemically delivered G-1 was well tolerated in PDAC bearing mice, significantly prolonged survival, and markedly increased the efficacy of PD-1 targeted immune therapy. We detected GPER protein in a majority of spontaneous human PDAC tumors. These data, coupled with the wide tissue distribution of GPER, and our previous work showing that G-1 inhibits melanoma, suggest that GPER agonists may be useful against many different cancer types.