Abstract C155: Inhibition of TAK1 promotes apoptosis in KRAS and Wnt pathway codependent colon cancers.

Abstract

Abstract Colorectal cancers frequently harbor KRAS mutations but KRAS-mutant cancers are refractory to conventional and targeted therapeutics. The primary aim of this study was to identify novel therapeutic strategies to target KRAS-mutant colon cancers. Firstly, we found that a subset of KRAS-mutant colorectal cancer cell lines are dependent upon KRAS signaling for survival. Secondly, we found that KRAS-dependent colorectal cancer cells require the TAK1 kinase (MAP3K7) for sustained viability. TAK1 depletion or the small molecule TAK1 kinase inhibitor 5Z-7-oxozeaenol results in profound apoptotic cell death in KRAS-dependent cells. Lastly, we noted that sensitivity to TAK1 disruption is associated with enhanced Wnt signaling resulting from APC mutations combined with KRAS hyperactivation. This effect can be attributed in part to a KRAS-mediated activation of BMP signaling, leading to TAK1 activation. TAK1 then directly regulates Wnt signaling specifically in KRAS-dependent cells. In primary human colorectal cancers, expression of a gene signature derived from TAK1-dependent cell lines is correlated with APC and KRAS mutational status. Thus, our studies reveal TAK1 inhibition as a potential therapeutic strategy for the generally treatment-refractory subset of colorectal cancers that are driven by the KRAS and Wnt pathways. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C155.