Abstract 2958: ONC206, an imipridone derivative, induces cell death through activation of the integrated stress response in serous endometrial cancer in vitro

Objectives: ONC206 (Oncoceutics) is a selective dopamine receptor D2 (DRD2) antagonist and an analogue of ONC201, an imipiridone currently being investigated in phase II clinical trials for serous endometrial cancer (EC). ONC206 has been shown to inhibit cell proliferation through activation of the integrated stress response (ISR) and apoptosis in brain, breast, and colorectal cancer cell lines. Thus, we investigated the efficacy of ONC206 for serous EC as well as its underlying mechanism of action. Methods: The serous EC cell lines, ARK1 and SPEC-2, were used. Cellular proliferation was measured using MTT assay. Cleaved caspase-3 and 9, markers of apoptosis, were assessed by ELISA assays. Adhesion and invasion were assessed by laminin and wound healing assays, respectively. Relative In vitro ISR was estimated by ROS and JC-1 assays. Western immunoblotting evaluated effects of ONC206 on proteins central to cellular stress and invasion. All statistical analyses were performed using the software Prism 8 (GraphPad). Results: ONC206 inhibited cellular proliferation in a dose-dependent manner and was more potent than ONC201 in ARK1 (IC50=0.33uM vs IC50=1.59uM) and SPEC-2 (IC50=0.24uM vs IC50=0.81uM) cell lines. Treatment with ONC206 decreased JC-1 fluorescence (p=0.001-0.01), and increased ROS production (p