Abstract 5512: TIC10/ONC201 in combination with ceralasertib exhibits potent synergy in high grade serous ovarian cancer cells

Abstract

High-grade serous ovarian cancer (HGSOC) is the most common and malignant form of ovarian cancer. Although patients with HGSOC are likely to respond to treatment, it is common for the cancer to recur and become resistant to treatment, therefore there is a need to develop new targets and novel combinations to increase patient survival rates. ATRi’s (Ataxia telangiectasia and Rad3 related inhibitors) have shown efficacy in HGSOC. Considering ATRi’s have shown moderate efficacy as a single treatment in HGSOC patients, we hypothesized that combining ATRi’s with ONC201 would enhance efficacy. ONC201 is a pro-apoptotic TRAIL-inducing compound that activates the integrated stress response and inactivates the Akt pathway which is upregulated in over 70% of HGSOC. Inactivation of the Akt pathway may result in a synergistic effect that could be translated for use in patients with HGSOC. Three HGSOC cell lines were treated with the novel drug combination of ceralasertib (ATRi) and ONC201 and CellTiterGLO viability assays were performed after 72 hours to evaluate the synergistic effect of combination treatment. Western blots were performed to investigate the synergistic effect of combination treatment on the Akt pathway as well as expression of the cellular metabolic stress protein ATF4. Cytokine profiling using the Luminex 200 technology was performed to study treatment-induced changes in the tumor microenvironment. Cell viability after ceralasertib and ONC201 combination treatment showed synergy in HGSOC cell lines (OVCAR3, KURAMOCHI, TOV21G). In TOV21G cell line, combination studies of ONC201 and ceralasertib calculated by compusyn software demonstrated a synergistic effect of both drugs, Combination indexes below one were observed at concentration of 0.008-2 μM of ceralasertib with 0.31-5 μM of ONC201 with the best combination index of 0.65. We similarly observed synergy in the two other cell line between ONC201 and ceralasertib. Western blotting showed reduction in total Akt and Erk expression and an increase in ATF4, consistent with the observed synergetic effect of ceralasertib and ONC201 combination. Our ongoing studies are exploring potential mechanisms of synergy between ceralasertib and ONC201 and effects on immune–mediated killing of HGSOC cells. Our results suggest a rational and potentially effective novel therapy combination of ATRi ceralasertib and ONC201 that maybe further developed for HGSOC. Citation Format: Maryam Ghandali, Kadir Mert Selvi, Kelsey E. Huntington, Andrew George, Anna Ochsner, Benedito A. Carneiro, Donn S. Dizon, Wafik S. El-Deiry. TIC10/ONC201 in combination with ceralasertib exhibits potent synergy in high grade serous ovarian cancer cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5512.