Sunday, January 29, 2023
1/29/2023
Project Summary/Abstract The overarching goal of our research program is to develop small-molecule anticancer drugs. We focus herein on a new chemical method to control aberrant Wnt/ß-catenin signaling that drives tumorigenesis and metastasis of many cancers, in particular, colorectal cancer (CRC). CRC affects about 4% of the population and caused ~60,000 deaths in 2021. Despite decades of effort, drugging this oncogenic pathway has not been successful. In 2009, we reported for the first time that Wnt/ß-catenin signaling can be intercepted by small molecules. Catalytic inhibition of tankyrases prevents the turnover of the Axin, which leads to a rapid accumulation of Axin. The accumulated Axin then stabilizes the ß-catenin destruction complex (DC) to facilitate the degradation of ß-catenin. However, using this strategy to treat cancer has not been successful. Recent studies suggest that tankyrases can, paradoxically, support Wnt/ß-catenin signaling through molecular scaffolding. The unexpected dichotomous mode of action potentially explains the unsatisfactory outcomes of various preclinical studies of tankyrase inhibitors. Although the mechanism by which tankyrases sustain Wnt/ß- catenin signaling is not clear, mounting evidence suggests that the tankyrase aggregation is responsible for it. In this study, we will develop a chemical strategy to control the catalysis-independent function of tankyrases. We will then use this new tool to study how tankyrases affect the dynamic assembly of DC. We will further use a proteomic approach to delineate the catalytic and scaffolding functions of tankyrases with detailed characterization of their mode of action. This work will help us understand how tankyrases control multiple signaling pathways important to cancer. Additionally, we will compare the responsiveness of a large panel of immortalized human colonic epithelial cell lines and CRC cell lines toward tankyrase inhibition and depletion. We will then corroborate the results with in vivo studies. Correlating the cellular sensitivity with their genetic background will provide potential biomarkers and inform therapeutic strategies for cancers. Overall, this project will address the unsolved issue in drugging the Wnt/ß-catenin pathway and improve our understanding of how tankyrases control Wnt/ß-catenin signaling.
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