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Ref Type Journal Article
PMID (19759537)
Authors Huang SM, Mishina YM, Liu S, Cheung A, Stegmeier F, Michaud GA, Charlat O, Wiellette E, Zhang Y, Wiessner S, Hild M, Shi X, Wilson CJ, Mickanin C, Myer V, Fazal A, Tomlinson R, Serluca F, Shao W, Cheng H, Shultz M, Rau C, Schirle M, Schlegl J, Ghidelli S, Fawell S, Lu C, Curtis D, Kirschner MW, Lengauer C, Finan PM, Tallarico JA, Bouwmeester T, Porter JA, Bauer A, Cong F
Title Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling.
Journal Vol Issue Date Pages Journal Short Title
Nature 461 7264 2009 Oct 1 614-20 Nature
URL
Abstract Text The stability of the Wnt pathway transcription factor beta-catenin is tightly regulated by the multi-subunit destruction complex. Deregulated Wnt pathway activity has been implicated in many cancers, making this pathway an attractive target for anticancer therapies. However, the development of targeted Wnt pathway inhibitors has been hampered by the limited number of pathway components that are amenable to small molecule inhibition. Here, we used a chemical genetic screen to identify a small molecule, XAV939, which selectively inhibits beta-catenin-mediated transcription. XAV939 stimulates beta-catenin degradation by stabilizing axin, the concentration-limiting component of the destruction complex. Using a quantitative chemical proteomic approach, we discovered that XAV939 stabilizes axin by inhibiting the poly-ADP-ribosylating enzymes tankyrase 1 and tankyrase 2. Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway. Thus, our study provides new mechanistic insights into the regulation of axin protein homeostasis and presents new avenues for targeted Wnt pathway therapies.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
XAV939 XAV939 8 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
XAV939 XAV-939 Tankyrase Inhibitor 11 XAV939 selectively inhibits Wnt/beta-catenin-mediated signaling by inhibiting tankyrase1/2, thus stabilizing axin and stimulating beta-catenin degradation (PMID: 19759537, PMID: 32681294).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
APC inact mut colorectal cancer sensitive XAV939 Preclinical Actionable In a preclinical study, XAV939 inhibited growth of colorectal cancer cells harboring APC inactivating mutations in culture (PMID: 19759537). 19759537