Variable GLP-1 receptor expression across diverse neuroendocrine neoplasms: implications for incretin therapies

Neuroendocrine neoplasms (NENs) are rare cancers originating in various organs and are further classified as well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). Commonly used drugs such as proton pump inhibitors can promote gastric NEN growth. Nowadays, incretin mimetic drugs such as glucagon-like peptide 1 receptor (GLP-1R) agonists have gained extensive popularity for the treatment of diabetes and obesity. These drugs target GLP-1R, and their use in neuroendocrine cancer patients with medullary thyroid carcinoma (thyroid NET) or multiple endocrine neoplasia syndrome type 2 is deemed contraindicated. Previous studies investigated GLP-1R expression in small subsets of NENs. Here, we assessed GLP-1R expression by immunohistochemistry in a large collection of 576 patient NENs from 13 sites of origin. We identified that 7% of NENs stained positive for GLP-1R. They were from five NEN types: duodenal NETs (dNETs), gastric NETs, pancreatic NETs, pheochromocytomas, and lung NETs. We then validated the dNET spheroids for response to an incretin mimetic drug and found activation of the MAPK pathway and growth. While GLP-1R agonists are contraindicated in patients with thyroid NETs, none of our 29 thyroid NETs expressed GLP-1R. Hence, in contrast to rodent studies, GLP-1R agonists may have little effect on human thyroid NETs since they do not express the receptor. Interestingly, ileal NETs also showed no expression of GLP-1R. More preclinical research examining potential oncogenic effects of incretin mimetics on the five subtypes of GLP-1R-positive NENs is needed to better understand their safety.