Therapeutic Activation of G Protein-Coupled Estrogen Receptor 1 in Waldenström Macroglobulinemia

Activation of G protein-coupled estrogen receptor 1 (GPER1) is an attractive therapeutic strategy to treat a variety of human diseases, including cancer. Here, we show that GPER1 is remarkably upregulated in tumor cells derived from different cohorts of Waldenström Macroglobulinemia (WM) patients respect to normal B cells. Using the clinically relevant GPER1-selective small-molecule agonist G-1 (also named Tespria), we demonstrate that pharmacological activation of GPER1 leads to G2/M cell cycle arrest and apoptosis both in vitro and in vivo in animal model, even in the context of the protective bone marrow milieu. We report that activation of GPER1 triggers the TP53 pathway, which remains actionable during WM progression. This study identifies a novel druggable target in WM and paves the way for the clinical development of the GPER1 agonist G-1. To investigate the activity of GPER1 in Waldenström Macroglobulinemia, we performed gene expression profiling using Affymetrix GeneChip analysis in BCWM-1 WM cell line treated with GPER1 selective agonist (G-1) compared to untreated cell line. Duplicate samples were analyzed for each condition.