Endometrial cancer is the most frequent type of gynecological tumor in the United States. Hysterectomy, the surgical removal of the uterus, is the main therapy for endometrial cancer, but this is not an option for women seeking to preserve their fertility. In cases of early-stage endometrial cancer and endometrial hyperplasia, hormonal therapy is a vital nonsurgical option. However, progesterone (P4) resistance robs women of the option to choose hormone therapy to preserve their uterus. Therefore, developing nonsurgical treatments for endometrial cancer remains an essential goal for women who wish to maintain endometrial functions and women in high-risk surgical conditions. Mitogen-inducible gene 6 (MIG-6) acts as a tumor suppressor during endometrial tumorigenesis and as a P4 target gene in humans and mice. We developed mice with the conditional knockout of Mig-6 in all uterine compartments (Pgrcre/+Mig-6f/f; Mig-6KO) and endometrial epithelial cell-specific Mig-6 knockout (Sprr2fcre/+Mig-6f/f; Mig-6Ep-KO) mice. P4 treatment abated the development of endometrial hyperplasia and restored morphological and histological characteristics of the uterus of Mig-6Ep-KO mice, but Mig-6Ep-KO mice showed P4 resistance. P4 treatment reduced cell proliferation which was accompanied by decreased AKT signaling. In order to investigate the inhibition effect of AKT/mTOR signaling as non-surgical treatment on P4-resistant endometrial hyperplasia, we treated Mig-6KO and Mig-6Ep-KO mice with either: 1) vehicle (PBS); 2) MK-2206 (360 mg/kg, once a week); or 3) everolimus (10mg/kg daily) at 10 weeks old (n=6/treatment/genotype) for 1 month. MK-2206 has completed phase II trials and inhibits AKT phosphorylation. Everolimus is FDA-approved mTOR inhibitor. The vehicle group of Mig-6KO and Mig-6Ep-KO mice manifested the endometrial hyperplasia phenotype. In contrast, IHC analysis showed that the groups receiving MK-2206 or everolimus experienced significantly decreased AKT phosphorylation and phosphorylated S6 levels, respectively, and decreased epithelial proliferation, resulting in restoration of normal uterine histology. These data suggest that everolimus and MK-2206 may be new non-surgical treatment options for P4-resistant endometrial hyperplasia. This information may help guide more effective non-surgical interventions in the future. The project described was supported by Grant Number P50CA098258 from the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.

Citation Format: Tae Hoon Kim, Jae-Wook Jeong. Everolimus and MK-2206 reverse P4-resistant endometrial hyperplasia in Mig-6 mutant mice [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO041.