The anti-tumor efficacy of combining oral ATR kinase inhibitor ceralasertib with TIC10/ONC201, an oral Akt/ERK inhibitor, TRAIL pathway and integrated stress response inducer, in prostate cancer treatment

Abstract Prostate cancer is the most common cancer and the second leading cause of cancer death among men in the United States. There are 268,490 estimated new cases and 34,500 estimated deaths in 2022 according to the NIH. Patients with metastatic castration resistant prostate cancer (mCRPC) have a poor prognosis and the current treatment options show limited efficacy. From the TRAP trial, 20% of mCRPC patients are reported to bear DNA repair defects. Ceralasertib, formerly known as AZD6738, is a potent and selective orally bioavailable inhibitor of the ataxia tenlangiectasia and Rad3-related (ATR) kinase, which is involved in DNA repair in response to DNA damage and replication stress. Ceralasertib’s antitumor activity as a monotherapy in treating prostate cancer is moderate. Thus, we investigated a combination therapy of ceralasertib with ONC201, a potent and cytotoxic orally bioavailable inhibitor of the serine/threonine protein kinase Akt and extracellular signal-regulated kinase (ERK). Upon administration, ONC201 can induce tumor cell apoptosis mediated by tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and activate integrated stress response (IRS). Preliminary results demonstrate synergistic activity with the combination therapy in vitro using CellTiterGLO viability assay 72 hours in a 96 well plate post treatment. Ongoing studies using western blotting and cytokine profiling are intended to illustrate the mechanism behind the proven synergy. Our results aim to solve the overarching need in developing novel therapeutic strategies to overcome resistance in current prostate cancer treatments. Citation Format: Yutong Xia, Maximilian P. Schwermann, Andrew George, Anna Ochsner, Benedito A. Carneiro, Wafik S. El-Deiry. The anti-tumor efficacy of combining oral ATR kinase inhibitor ceralasertib with TIC10/ONC201, an oral Akt/ERK inhibitor, TRAIL pathway and integrated stress response inducer, in prostate cancer treatment [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 1070.