Abstract 5195: Modulating the UPR using the impridone ONC201 to change the impact of radiation on prostate cancer cells

Abstract

Abstract Prostate cancer is the highest incidence non-cutaneous cancer in men, and a significant cause of cancer mortality. Localized disease is treated with surgery or radiotherapy and whilst androgen deprivation therapy can extend survival in the subset of cases that progress, metastatic disease is incurable. We have found that oncogenic drivers of prostate cancer, as well as therapy, lead to changes in the activation of prostate cancer cell stress signaling pathways and in particular the unfolded protein response (UPR). We have previously reported that the androgen receptor sustains the cytoprotective activity of the IRE1-XBP1 arm of the UPR and represses the activation of the PERK-ATF4 arm. We showed that treating prostate cancer cells with radiation leads to the activation of all three arms of the UPR, culminating in treatment resistance in surviving cells. In this study we assess whether the activation of the UPR in response to radiation mirrors the immunogenic/inflammatory response, which is known to occur in an initially acute apoptotic phase before resolving to a chronic sustainable level. Further we have evaluated the impact of combining radiation with ONC201, a novel anti-cancer small molecule in clinical trials that is an activator of the UPR, on the viability of prostate cancer. We find that ONC201 has a delayed cytotoxic effect as a single agent, with the impact on viability occurring from 72 hours onwards at low microMolar concentrations. However activation of multiple arms of the UPR occurs earlier and is detectable at 24 hours for ATF4, ATF6 and IRE1-XBP1 at the protein/mRNA levels. This time difference creates a window in which to introduce sequential administration of radiation to test ONC201 as a primer for cytotoxic response radiation. We have undertaken this work in a panel of cell-lines (PC3, DU145 and AR-expressing cell-lines) in which we have also knocked down key regulators (PERK, IRE1, CHOP) of separate arms of the UPR. This represents the first in vitro study to characterise the impact of ONC201 on the radiation-responsiveness of prostate cancer cells. Citation Format: Francesca Amoroso, Adam Pickard, Alice McNaney, Rohinton Tarapore, Joshua E. Allen, Ian G. Mills. Modulating the UPR using the impridone ONC201 to change the impact of radiation on prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5195. doi:10.1158/1538-7445.AM2017-5195