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Ref Type Journal Article
PMID (28611108)
Authors Zeng S, Seifert AM, Zhang JQ, Cavnar MJ, Kim TS, Balachandran VP, Santamaria-Barria JA, Cohen NA, Beckman MJ, Medina BD, Rossi F, Crawley MH, Loo JK, Maltbaek JH, Besmer P, Antonescu CR, DeMatteo RP
Title Wnt/β-catenin Signaling Contributes to Tumor Malignancy and Is Targetable in Gastrointestinal Stromal Tumor.
Journal Vol Issue Date Pages Journal Short Title
Molecular cancer therapeutics 16 9 2017 09 1954-1966 Mol Cancer Ther
URL
Abstract Text Gastrointestinal stromal tumor (GIST) is the most common type of sarcoma and usually harbors either a KIT or PDGFRA mutation. However, the molecular basis for tumor malignancy is not well defined. Although the Wnt/β-catenin signaling pathway is important in a variety of cancers, its role in GIST is uncertain. Through analysis of nearly 150 human GIST specimens, we found that some human GISTs expressed β-catenin and contained active, dephosphorylated nuclear β-catenin. Furthermore, advanced human GISTs expressed reduced levels of the Wnt antagonist DKK4. Accordingly, in human GIST T1 cells, Wnt stimulation increased β-catenin-mediated transcriptional activity in a reporter assay as well as transcription of the downstream target genes Axin2 and CCND1 In contrast, DKK4 overexpression in GIST T1 cells reduced Wnt/β-catenin signaling. In addition, we showed that nuclear β-catenin stability was partially regulated by the E3 ligase COP1, as demonstrated with coimmunoprecipitation and COP1 knockdown. Three molecular inhibitors of the Wnt/β-catenin pathway demonstrated antitumor efficacy in various GIST models, both in vitro and in vivo Notably, the tankyrase inhibitor G007-LK alone had substantial activity against tumors of genetically engineered KitV558Δ/+ mice, and the effect was increased by the addition of the Kit inhibitor imatinib mesylate. Collectively, our findings demonstrate that Wnt/β-catenin signaling is a novel therapeutic target for selected untreated or imatinib-resistant GISTs. Mol Cancer Ther; 16(9); 1954-66. ©2017 AACR.

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