Abstract 4397: Tak-1 inhibition re-sensitizes cancer cells to TNFα

Abstract

Abstract Identifying new pharmaceutical targets in cancer has been a long lasting goal of academia. Complex genomic changes coupled with a cancer cell's ability to adapt make tumors particularly difficult to target. To this end, we have identified the TAK1 kinase in the TNFα pathway as a potential mediator of cell survival or apoptosis. Here we evaluate the apoptotic effects of a novel TAK1 inhibitor, Takinib. The selectivity of Takinib was established with an IC50 of 9nm for TAK1, followed by an IC50 for IRAK4 and IRAK1 at 120nm and 390nm respectively. Treatment of MDA-MB-231 cells with Takinib on its own is not sufficient to induce consequential cell death. However, combination therapy with TNFα induces caspase 3/7 activity and subsequent cell death in a dose-dependent manner. Genetic knock out of TAK1 expression in MDA-MB-231 cells with the CRISPR/Cas9 system significantly sensitized previous resistant cells to TNFα. Furthermore, we have shown that activation of human THP-1 cells with LPS is sufficient to produce TNFα levels necessary to facilitate Takinib mediated cell death, indicating that potential immunotherapy applications may be possible. Together these findings support the idea that TAK1 may be an effective target in the TNFα pathway, shifting the cellular mechanisms from pro survival to pro apoptosis. Citation Format: Scott Scarneo, Madeline Sell, Juliane Totzke, David Carlson, Phillip Hughes, Tim Haystead. Tak-1 inhibition re-sensitizes cancer cells to TNFα [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4397.