GLP1R expression in prostate cancer patients and effects of GLP1R agonism on prostate cancer cells.

Abstract

182 Background: As a disease of aging, metabolic co-morbidities are managed concurrently with prostate cancer. Recent FDA approvals have launched widespread use of GLP1 receptor agonist semaglutide for Type II Diabetes Mellitus and obesity. Mechanistically, semaglutide primarily activates GLP1 receptors in the pancreas. However, GLP1R is also expressed in advanced prostate cancer tissues where GLP1 agonism could affect signaling and disease progression. Understanding the effects of semaglutide treatment in prostate cancer is critical to gain a complete picture of the systemic effects this drug and potentially expose additional contexts where semaglutide can be therapeutically valuable in this disease space. Methods: RNA-sequencing data was accessed from dbGaP (consolidated, n=664) and Gene Expression Omnibus (GSE204057, n=55) to assess GLP1R expression in prostate cancer patients. Bioinformatics analyses were utilized to identify signaling pathways associated with GLP1R expression. Proliferation, metabolism, and signaling after GLP1R agonism with semaglutide were assessed in vitro in prostate cancer cell line models using incucyte, Seahorse, and a kinase proteome profiler array. Results: We identified GLP1R expression in advanced prostate cancer samples including 145/310 (46.8%) of metastases, 59/115 (51.3%) of castration-resistant prostate cancer (CRPC), and 9/15 (60%) of neuroendocrine prostate cancer (NEPC), where it was associated with Notch and Hedgehog Signaling. Semaglutide treatment in pre-clinical prostate cancer models resulted in decreased cell proliferation, decreased glycolytic function, and decreased activation of kinase-mediated signaling. This overall suppression of signaling downstream of GLP1R is consistent with Gai-coupled GPCR signaling, which was confirmed using a cAMP assay. Interestingly, in a trans-differentiation model there was a significant negative correlation between GLP1R and AR expression. Further, proliferation of prostate cancer cells was significantly decreased with combination treatment of enzalutamide with semaglutide compared to either treatment alone. Conclusions: GLP1R was expressed in advanced prostate cancer patients and treatment with semaglutide suppressed growth, metabolism, and signaling. This is clinically significant due to concurrent treatment for metabolic co-morbidities in men with prostate cancer. Our preliminary data shows that co-targeting AR and GLP1R decreased cell growth, suggesting GLP1R agonism may be therapeutically useful in combination with androgen receptor antagonists in advanced prostate cancer.