Abstract 3188: MEK and TAK1 signaling interactions coordinately regulate inflammation and apoptosis in KRAS dependent colon cancer cells
Authors: McNew Kelsey L. , Whipple William J. , Mehta Anita K. , Grant Trevor , Singh Anurag 
Published: August 2015

The KRAS protooncogene is mutated in 40 to 50% of colon cancers. In an effort to identify strategies to treat KRAS mutant colon cancers, we previously implicated the TGF-β activated kinase (TAK1) as a candidate therapeutic target that promotes the survival of KRAS dependent cancers. In follow-up studies, we have explored and investigated the detailed mechanistic basis for TAK1 mediated survival signaling in KRAS dependent cancer cells. Using proteomic and transcriptomic analyses of proinflammatory signaling mediators, we have uncovered complex autocrine/paracrine signaling loops that are constitutively activated in KRAS dependent colon cancer cells. A central mediator of these signaling loops is the BMP7-BMP receptor (BMPR1A) pathway, which functions coordinately with oncogenic KRAS to drive TAK1 and NF-κB mediated transcriptional upregulation of proinflammatory cytokines such as GM-CSF, CCL5/RANTES and IL-8. Conversely, a number of cytokines and cytokine regulators are negatively regulated by KRAS-BMPR signaling interactions, including CXCL9/MIG and IL1RN.

We previously showed that TAK1 inhibition with a small molecule agent, 5Z-7-oxozeaenol promotes apoptosis in colon cancer cells. We have now determined that 5Z-7-oxozeaenol, in addition to irreversibly inhibiting TAK1 kinase activity, also transiently inhibits the MEK kinase. Therefore, combined TAK1/MEK inhibition explains the potent killing effects that we have observed in KRAS dependent colon cancer cells. To test this empirically, we have used 2 selective kinase inhibitors targeting each respective kinase, AZ-TAK1 and AZD6244 to show either single agent can induce apoptotic cell selectively in KRAS dependent cells, with TAK1 inhibition resulting in stronger killing effects. Importantly, treatment of KRAS dependent colon cancer cells with combinations of AZ-TAK1 and AZD6244 results in additive killing effects, revealing a potential therapeutic strategy for KRAS dependent cancers in the clinic.

Mechanistically, MEK and TAK1 converge on the control of NF-κB and canonical Wnt-dependent transcriptional activities. Surprisingly, we find that NF-κB and Wnt signaling mutually antagonize each other in terms of cytokine expression to create a finely-tuned balance between pro-death and pro-survival signals. We hypothesize that, as a consequence, these balanced signals allow for both efficient maintenance of tumor cell survival and as well as for communication with stromal components in the tumor microenvironment. Thus, KRAS, MEK or TAK1 blockade results in a tipping of the balance to favor pro-death signals.

Citation Format: Kelsey L. McNew, William J. Whipple, Anita K. Mehta, Trevor Grant, Anurag Singh. MEK and TAK1 signaling interactions coordinately regulate inflammation and apoptosis in KRAS dependent colon cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3188. doi:10.1158/1538-7445.AM2015-3188