Abstract 1813: Evaluation of TBK1 as a novel cancer target in the K-Ras pathway

TBK1 (TANK-binding kinase 1) is a serine/threonine kinase best known for its role in mediating the innate immune response through modulation of the interferon and NF-kB pathways. TBK1 has also been implicated in supporting cancer cell survival and transformation as the downstream effector of the small GTPase RalB, and is overexpressed in lung, breast and colon tumors. Recently, a high-throughput RNAi screen identified TBK1 as a synthetic lethal partner of oncogenic K-Ras, suggesting that small molecule inhibition of TBK1 may provide a novel therapeutic strategy for K-Ras mutant tumors. Given the high tractability of kinases as drug targets, we sought to confirm that kinase inhibition recapitulated the synthetic lethal effects observed with shRNA silencing. We examined two small molecule inhibitors of TBK1, BX795 (6 nM) and GSK2292978A (4 nM), in a panel of lung, pancreas and colon cancer cell lines. We found only a small subset of lines that were sensitive to TBK1 inhibition and this sensitivity did not correlate with K-Ras dependence. We then used K-Ras and TBK1 siRNA in a similar panel of cell lines. As anticipated, knockdown of K-Ras using siRNA produced significant growth and signaling defects in K-Ras dependent cell lines. In contrast, knockdown of TBK1 did not result in a significant alteration of growth in any of our cell lines. Neither TBK1 siRNA nor TBK1 inhibitors revealed a sensitivity that correlated with K-Ras dependence in our lung, pancreatic, or colorectal cancer cell lines. Our data disputes the proposed synthetic lethal relationship of oncogenic K-Ras and TBK1 and does not support development of TBK1 inhibitors for treatment of K-Ras driven tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1813. doi:1538-7445.AM2012-1813