Objectives: Olaparib is a poly ADP-ribose polymerase inhibitor (PARPi) approved for use as maintenance and treatment in advanced and recurrent ovarian cancer (OC). The imipridone ONC206, a chemical derivative of ONC201, is a bioavailable dopamine receptor D2 (DRD2) antagonist that has anti-tumorigenic effects via induction of apoptosis and activation of the integrated stress response. ONC206 exhibits differentiated receptor pharmacology, nanomolar potency, and enhanced bioavailability relative to ONC201. Both olaparib and imipridones (i.e. ONC201) are being evaluated in OC clinical trials, but have yet to be explored in combination. Thus, we sought to examine the effects of olaparib in combination with ONC206 in human OC cell lines.

Methods: The OC cell lines, OVCAR3 and OVCAR5, were used. Both cell lines were treated with varying doses of ONC206 (Oncoceutics) and olaparib (MedChemExpress) alone and in combination. Cell proliferation and apoptosis were assessed by MTT and cleaved caspase assays, respectively. Synergy between olaparib and ONC206 was evaluated by the combination index (CI) method of Chou-Talalay. Reactive oxygen species (ROS) was determined by DCFDA assay. Adhesion and migration were assessed by laminin and wound healing assays, respectively. Western blotting was performed to evaluate the effects of olaparib and ONC206 on apoptotic and invasion-related proteins in both OC cell lines.

Results: Both drugs inhibited OC cell proliferation in a dose-dependent manner after 72 hrs of exposure (IC50 for olaparib of 15-25 µM for both OVCAR3 and OVCAR5; IC50 1.5 µM and 0.4µM for ONC206 in OVCAR3 and OVCAR5, respectfully). Simultaneous exposure of ONC206 with olaparib resulted in a synergistic anti-proliferative effect (CI<1). Treatment with ONC206 plus olaparib increased cleaved caspase 3 activity and ROS production compared to controls, and the combination had greater effects than either drug alone (p<0.05). ONC206 and olaparib individually reduced OC cell adhesion and migration, with synergistic effects on adhesion/migration seen when used in combination (p<0.05). Western blotting found that ONC206 and olaparib both decreased expression of Bcl-XL, snail and vimentin compared to controls, and these effects were potentiated with dual therapy.

Conclusions: ONC206 in combination with olaparib resulted in synergistic anti-tumorigenic and anti-metastatic effects in OC cell lines, suggesting that this novel dual therapy may be worthy of further exploration in clinical trials in OC.

Citation Format: Gabrielle M. Hawkins, Sarah E. Paraghamian, Yali Fan, Wenchaun Sun, Xin Zhang, Varun Prabhu, Joshua E. Allen, Chunxiao Zhou, Victoria L. Bae-Jump. Olaparib potentiates the anti-proliferative and anti-metastatic effects of ONC206 in ovarian cancer cells [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 5336.