Abstract 4752: The combination of GLP1-R agonists and progestins enhances endometrial cancer cell killing through membrane receptor crosstalk

Obesity is a major risk factor for endometrial cancer, and glucagon like peptide-1 receptor (GLP-1R) agonists such as semaglutide may be helpful to achieve weight loss. Conservative treatment of endometrial cancer includes hormone therapy with progestins for women who wish to preserve their uterus. Our previous work showed a significant reduction in viability of multiple endometrial cancer cell line and organoid models in response to the combination treatment of semaglutide and levonorgestrel, and identified a positive feedback loop between GLP-1R and progesterone receptor (PR) signaling. Here, we further explored mechanisms underlying the enhanced signaling, using confocal microscopy to show the co-localization of membrane PR (Progesterone Receptor Membrane Component 1; PGRMC1) and GLP1-R in response to semaglutide + progesterone combined treatment. We also found that semaglutide alone (100nM) induces the translocation of PR to the nucleus within 30 minutes. We are undergoing microarray analyses to assess specific phosphorylation events as well as RNA sequencing occurring downstream to identify the signaling molecules and transcripts activated by dual treatment. These studies highlight the potential of semaglutide to improve the anti-cancer effects of progestins, and, importantly, may reduce recurrences that can occur with progestin therapy alone. Citation Format: Lane E. Smith, Jamie L. Padilla, Geneva L. Williams, Kristina Thiel, Kimberly K. Leslie. The combination of GLP1-R agonists and progestins enhances endometrial cancer cell killing through membrane receptor crosstalk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4752.