New insight into signaling contexts for the administration of the imipridone ONC201 to prostate cancer cells

Abstract Prostate cancer is the most common non-cutaneous cancer in men and a notable cause of cancer mortality. In the majority of the cases localised disease radical treatment consists of surgery or radiotherapy. Upon progression androgen deprivation therapy can extend survival however metastatic disease is incurable. The prostate is a specialized accessory gland with a high secretory capacity. As prostate cancer develops and treatment resistance emerges, the unfolded protein response (UPR) is an important adaptive biology which co-amplifies with key cancer drivers1. The UPR can be cytoprotective but when acutely activated can lead to cell death. In this study we sought to enhance the acute activation of the UPR using radiation and ONC201, previously reported to be a UPR activator2. We found that treating prostate cancer cells with ONC201 induced increases in the expression of components in all arms of the UPR - ATF4, ATF6 and IRE1-XBP1 - at protein and transcript levels at a 24-hour time point and this was followed at 72 hours by cell death. This delay in the induction of cell death provided a time window for the short-term administration of ONC201 to prime an enhanced cytotoxic response to radiation. Pre-treatment with ONC201 for 24 hours followed by withdrawal and subsequent irradiation led to enhanced cytotoxicity assessed by cell viability and clonogenic assays. In order to decipher the impact of ONC201 and radiation we undertook RNA-seq under a range of treatment conditions. We noted a durable suppression of transcripts encoding cell cycle regulatory genes when ONC201 pre-treatment was used to enhance radiation response and this translated into cell cycle arrest and induction of both necrotic and apoptotic cell death as assessed by flow cytometry. Pathway analysis of the RNA-seq suggests alternative targets that could replicate this priming effect to enhance radiation response. 1.Storm, M. et al., Oncotarget 7(33): 54051-54066 (2016). 2.Allen, J. et al., Oncotarget (2016). doi:10.18632/oncotarget.11814. Citation Format: Francesca Amoroso, Adam Pickard, Kimberly Glass, Rohinton Tarapore, Josh Allen, Ian G. Mills. New insight into signaling contexts for the administration of the imipridone ONC201 to prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2928.