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. ONC201 is the first clinical bitopic antagonist of dopamine receptor D2 (DRD2), that is well tolerated and currently being investigated in several clinical trials for oncology. ONC206 is a chemical derivative of ONC201 with the same impridone core structure, which is also a DRD2 antagonist that exhibits distinct receptor pharmacology and nanomolar potency in various preclinical cancer models. 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 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 dose-dependent manner. 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, and multiple mitochondrial proteins associated with mitochondrial ATP synthesis including MTCO1, and TFAM than the control cells 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 metabolic reprogramming and increased apoptosis. Moreover, by knocking-out DRD2, USC cells became more resistant to ONC206 treatment. This suggested that the effect of ONC206 is likely mediated through its binding to DRD2. ONC206 also showed a synergistic effect with paclitaxel in vitro. 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 S. Tarapore, Joshua E. Allen, Karen H. Lu, Samuel C. Mok. Novel imipridone ONC206 inhibits cell proliferation and induces apoptosis in uterine serous cancer through altering MAPK/AKT signaling network and metabolic reprogramming [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5321.