GLP1 receptor agonism alters growth and therapeutic response in prostate cancer.

The burgeoning metabolic benefits of GLP1 receptor (GLP1R) agonists have led to their widespread use for treatment of type 2 diabetes mellitus and obesity. While the pharmacological GLP1R agonist semaglutide primarily activates GLP1R signaling in the pancreas, GLP1R is also expressed in advanced prostate cancer where GLP1R agonism could directly alter cellular signaling. Because metabolic disorders and their treatment are common among those with prostate cancer, understanding the effects of semaglutide in prostate cells is critical for deciphering its systemic effects and delineating potential impacts on prostate cancer outcomes. In prostate cancer models, semaglutide decreased cell proliferation, glycolytic function, and phosphokinase-mediated signaling. This overall suppression of signaling downstream of GLP1R is consistent with inhibitory GPCR signaling, which was confirmed by reduced cAMP levels. Furthermore, cell proliferation was decreased with semaglutide alone and in combination with enzalutamide, supporting that GLP1R agonism may provide therapeutic benefit as a standalone treatment or to augment the therapeutic benefits of androgen receptor signaling inhibitors. Interestingly, in a trans-differentiation model (n = 55), GLP1R and AR expression were negatively correlated, while GLP1R and NEPC markers (DLL3, ASCL1) were positively correlated, suggesting an association between GLP1R and neuroendocrine differentiation. Bioinformatic analyses on publicly available patient RNA sequencing data (n = 664) identified significantly higher GLP1R expression in advanced prostate cancer vs benign prostate, where it was associated with negative Notch signaling. Taken together, our data support a model wherein GLP1R agonism blocks oncogenic signaling pathways and growth of prostate cancer cells, which could be exploited therapeutically for men with advanced prostate cancer.