Abstract B32: Targeting WNT signaling in vivo via Tankyrase inhibition

Abstract

Abstract Colorectal cancer (CRC) is the second leading cause of cancer-related death in the United States. Approximately 95% of CRCs show hyperactive WNT signaling, yet there are no targeted therapies that effectively suppress the WNT pathway. The majority (~80%) of these tumors harbor a mutation in APC, a scaffold component of the “destruction complex,” which is a critical negative regulator of WNT. Using genetically defined mouse models of CRC, we recently showed that restoring Apc function can induce WNT suppression and rapid and sustained disease regression. While there is no way to restore normal APC protein in human CRCs, it may be possible to restore the function of the APC-associated destruction complex by inhibiting Tankyrase (TNKS) enzymes. Tankyrase inhibitors have been shown to stabilize AXIN, prevent degradation of the destruction complex, and decrease levels of WNT signaling. While in vitro studies have shown promise, it is unclear whether TNKS inhibition could provide a therapeutic benefit in vivo. Some published work reports significant antitumor activity, while others suggest overt dose-limiting toxicity. Thus, while TNKS inhibition holds significant potential, it is not clear whether TNKS enzymes are a viable target for CRC therapy. To circumvent the limitations of drug delivery, potency, and specificity, we generated mice with inducible, fluorescent reporter-linked shRNAs targeting Tnks and its redundant family member Tnks2. Here we show that potent, simultaneous shRNA-mediated knockdown of both genes is sufficient to stabilize Axin in vivo, similar to treatment with a pan-TNKS inhibitor, XAV939. We show that Tnks1/2 knockdown stabilizes Axin and suppresses WNT signaling, but surprisingly, does not disrupt intestinal architecture. Importantly, Tnks1/2 silencing blocks hyperproliferation and tumor development in mice following Apc disruption. In contrast to current studies using small-molecule TNKS inhibitors, our work suggests that there is a viable therapeutic window of TNKS1/2 inhibition in vivo, and that this strategy enables control of hyperactive WNT signaling in CRC and other WNT-associated cancers. Citation Format: Emma M. Schatoff, Benjamin I. Leach, Miguel Foronda, Maria Paz Zafra, Lukas Dow. Targeting WNT signaling in vivo via Tankyrase inhibition [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr B32.