Abstract A119: Inhibition of IRE1-mediated pro-tumorigenic responses enhances the sensitivity of MDA-MB-231 cells to the novel arylurea-fatty acid CTU

Abstract

Abstract There is an unmet need for new agents with low toxicity for treatment of triple-negative breast cancer (TNBC) because current approaches are limited to toxic drug combinations of low efficacy. We recently identified an aryl-substituted fatty acid analogue, termed CTU, that effectively killed TNBC cells in vitro and in mouse xenograft models in vivo without producing toxicity (Rawling et al., 2017). However, there was a residual cell population that survived CTU. The present study evaluated the mechanism underlying residual cell survival. From RNA-seq profiling, a major regulated process in CTU-treated cells was activation of the unfolded response and endoplasmic reticulum (ER)-stress. The ER transmembrane protein inositol-requiring enzyme 1 (IRE1) is a central mediator of the unfolded response and ER-stress that was activated by CTU. IRE1 is also implicated as a pro-tumorigenic factor that can activate the expansion of tumor-initiating cells. From RNA-seq several pro-tumorigenic factors, including cyclooxygenase-2 and the cytokines IL6, IL8 and GM-CSF, were strongly activated in CTU-treated cells; this was confirmed by real-time RT-PCR and Western blot analysis. Using the non-adherent, in vitro colony-forming mammosphere assay, that enables the quantification of cell self-renewal, it was found that CTU expanded tumor-initiating cells. Co-treatment with an inhibitor of IRE1 impaired IRE1 kinase and IRE1 RNase activities, as reflected by decreases in phospho-p65 and XBP1s expression. IRE1 inhibition also prevented the activation of pro-tumorigenic factors and self-renewal by CTU. Taken together, the present findings suggest that inhibition of IRE1 may be a novel approach to optimise the activity of CTU in TNBC. Citation Format: Md Khalilur Rahman, Tristan Rawling, Yassir Al-Zubaidi, Hassan Choucair, Bala Umashankar, Yongjuan Chen, Kirsi Bourget, Stanton Tam, Charlotte Smith, Michael Murray. Inhibition of IRE1-mediated pro-tumorigenic responses enhances the sensitivity of MDA-MB-231 cells to the novel arylurea-fatty acid CTU [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A119. doi:10.1158/1535-7163.TARG-19-A119