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

Po Hien Ear; Sophia A. Hueser; Reese E. Townsend; Jessica E. Maxwell; Ellen Abusada; Carlos HF Chan; Dawn E. Quelle; Joseph S. Dillon; James R. Howe; Andrew M. Bellizzi

doi:10.1530/EO-25-0051

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

Journal article

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

Po Hien Ear, Sophia A. Hueser, Reese E. Townsend, Jessica E. Maxwell, Ellen Abusada, Carlos HF Chan, Dawn E. Quelle, Joseph S. Dillon, James R. Howe and Andrew M. Bellizzi

Endocrine oncology, Vol.5(1), e250051

11/10/2025

DOI: 10.1530/EO-25-0051

PMCID: PMC12648204

PMID: 41312422

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Abstract

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 the glucagon-like peptide 1 receptor (GLP-1R) agonists have gained extensive popularity for 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 NEN. 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 5 NEN types: duodenal NETs (dNET), 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 NET, 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 NET also showed no expression of GLP-1R. More preclinical research examining potential oncogenic effects of incretin mimetics on the 5 subtypes of GLP-1R positive NENs is needed to better understand their safety.

Details

Title: Subtitle: Variable GLP-1 receptor expression across diverse neuroendocrine neoplasms: Implications for incretin therapies
Creators: Po Hien Ear - University of Iowa
Sophia A. Hueser - University of Iowa
Reese E. Townsend - University of Iowa
Jessica E. Maxwell - The University of Texas MD Anderson Cancer Center
Ellen Abusada - University of Iowa
Carlos HF Chan - University of Iowa, Surgery
Dawn E. Quelle - University of Iowa
Joseph S. Dillon - University of Iowa
James R. Howe - University of Iowa
Andrew M. Bellizzi - University of Iowa
Resource Type: Journal article
Publication Details: Endocrine oncology, Vol.5(1), e250051
DOI: 10.1530/EO-25-0051
PMID: 41312422
PMCID: PMC12648204
NLM abbreviation: Endocr Oncol
ISSN: 2634-4793
eISSN: 2634-4793
Language: English
Electronic publication date: 11/10/2025
Date published: 11/10/2025
Academic Unit: Pathology; Surgery; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9985027359802771

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