Abstract PO044: A novel dopamine receptor D2 antagonist (ONC206) potentiates the effects of olaparib in endometrial cancer
Authors: Sarah E. Paraghamian, Gabrielle M. Hawkins, Wenchuan Sun, Yali Fan, Xin Zhang, Hongyan Suo, Varun Vijay Prabhu, Joshua E. Allen, Chunxiao Zhou, Victoria Bae-Jump
Journal: Clinical Cancer Research (2021)

Abstract Objectives: Poly ADP-ribose polymerase (PARP) inhibitors are effective therapies for patients with homologous recombination (HR) deficient tumors. While HR mutations are rare in endometrial cancers (ECs), emerging data suggests that loss of function of the tumor suppressor gene PTEN, which is mutated in 80% of endometrioid ECs, may also sensitize tumors to PARP inhibition. The imipridone ONC206 is an orally bioavailable dopamine receptor D2 antagonist that has anti-tumorigenic effects in EC via induction of apoptosis, activation of the integrated stress response and modulation of Akt signaling. Both PARP inhibitors and imipridones are being evaluated in EC clinical trials, but have yet to be explored in combination. We sought to examine the effects of the PARP inhibitor olaparib in combination with ONC206 in human endometrioid EC cell lines and in a mouse model of endometrioid EC. Methods: The ECC-1 and HEC-1 EC cell lines were used. Cell proliferation was assessed after exposure to varying doses of olaparib (MedChemExpress) and ONC206 (Oncoceutics) via the MTT assay. Synergy between olaparib and ONC206 was assessed by the combination index (CI) method of Chou-Talalay. Cellular stress was evaluated using the DCFH-DA assay. Apoptosis was assessed using the cleaved caspase-3 assay. Western immunoblotting was performed to determine effects of olaparib and ONC206 on apoptosis and the mTOR pathway. LKB1fl/flp53fl/fl mice were fed either a low-fat diet (10% of calories from fat, lean) or high-fat diet (60% of calories from fat, obese). Following EC onset, the mice were treated with ONC206 (100 mg/kg weekly orally), olaparib (25 mg/kg daily orally), or the combination for 4 weeks. Immunohistochemistry was used to assess Ki-67 expression in EC. Results: Both drugs inhibited cell proliferation in a dose-dependent manner (IC50 for olaparib of 15 µM for ECC-1 and 25 µM for HEC-1; IC50 for ONC206 of 3.3 µM for ECC-1 and 0.9 µM for HEC-1). Simultaneous exposure of EC cells to ONC206 and olaparib resulted in synergistic anti-proliferative effects (CI&amp;lt;1). Combination treatment with ONC206 and olaparib increased cellular stress and apoptosis in both cell lines (p=0.05-0.001), compared to either drug alone. Dual therapy with olaparib and ONC206 decreased expression of the anti-apoptotic protein Bcl-2 and decreased phosphorylation of S6, a downstream target of the mTOR pathway, with greater effects compared to either drug alone. The combination of ONC206 and olaparib led to a greater reduction in EC tumor weight in obese (91%) and lean (85%) mice compared to ONC 206 alone (obese 84% and lean 77%) or olaparib alone (obese 83% and lean 65%) (p&amp;lt;.05). ONC206 and olaparib significantly reduced Ki-67 expression in obese and lean mice, with more potent effects for the combination treatment. Conclusions: Olaparib and ONC206 had synergistic anti-tumorigenic effects in human endometrioid EC cell lines and in a mouse model of endometrioid EC, suggesting that this novel dual therapy may be worthy of further exploration in clinical trials in EC. Citation Format: Sarah E. Paraghamian, Gabrielle M. Hawkins, Wenchuan Sun, Yali Fan, Xin Zhang, Hongyan Suo, Varun Vijay Prabhu, Joshua E. Allen, Chunxiao Zhou, Victoria Bae-Jump. A novel dopamine receptor D2 antagonist (ONC206) potentiates the effects of olaparib in endometrial cancer [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 PO044.