Uterine serous carcinoma (USC) is the most aggressive subtype of endometrial cancer. Patients with advanced stage USC have poor survival rates and new treatment regimens are lacking. Recent clinical studies showed that imipridones constitute a novel class of agents with antitumor activities. Among them, ONC206, a novel orally bioavailable small molecule that has recently been shown to bind G protein-coupled receptor (GPCR)-dopamine receptor D2 (DRD2) by comprehensive GPCR screening, induces apoptosis in glioblastoma cells. However, the effects of ONC206 on USC progression and the mechanism of action have not been thoroughly explored. Using both in vitro and in vivo models, and multiple USC cell lines, the effects of ONC206 on cell proliferation, cell cycle progression, and apoptosis were determined. Reverse phase protein arrays (RPPAs) and Western blot analyses were used to determine the effect of ONC206 on the expression of key proteins in various signaling networks in ONC206 treated USC cells. The results showed that ONC206 suppressed USC cell proliferation and induces apoptosis in a does dependent manner. It increased the number of USC cells in the G1 phase of the cell cycle. Luciferase labeled USC cell ARK1-bearing mice treated with 100mg/kg ONC206 had significantly lower chemiluminescent signals than those treated with the control buffer. RPPA data showed that ONC206 treated USC cells had markedly lower expression signals in p38MAPK, p-AKT, p-S6, CDKs, and multiple mitochondrial proteins associated with mitochondrial ATP synthesis including MTCO1, SDHB, and HSPD1 than the control cells did. In addition, markedly higher expression levels of p-AMPK, Bim, and cleaved caspases were also observed in ONC206 treated cells than the control did. Significantly lower ATP levels and cytochrome c oxidase activities in ONC206 treated USC cells than in control cells were demonstrated by luminescent ATP detection assay kit and the cytochrome c oxidase assay kit. These data suggest that ONC206 suppresses USC progression through inhibiting MAPK/AKT network, which subsequently leads to cell cycle arrest, metabolic reprogramming and increased apoptosis. Further studies which demonstrate the optimal dosage and the efficacy of treatment of USC using ONC206 are warranted.

Citation Format: Chi Lam Au Yeung, Wen Hu, Li Zhang, Sammy Ferri-Borgogno, Rohinton Tarapore, Karen H Lu, Samuel C Mok. Novel imipridone ONC206 inhibits cell proliferation and induces apoptosis in uterine serous cancer through altering MAPK/AKT/AMPK signaling network and metabolic reprogramming [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C055. doi:10.1158/1535-7163.TARG-19-C055

©2019 American Association for Cancer Research.
2019
American Association for Cancer Research.