Wnt/β-catenin Signaling Contributes to Tumor Malignancy and Is Targetable in Gastrointestinal Stromal Tumor

Abstract

Gastrointestinal stromal tumor (GIST) is the most common type of sarcoma and usually harbors either a <i>KIT</i> or <i>PDGFRA</i> 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 <i>Axin2</i> and <i>CCND1</i> In contrast, <i>DKK4</i> 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 <i>in vitro</i> and <i>in vivo</i> Notably, the tankyrase inhibitor G007-LK alone had substantial activity against tumors of genetically engineered <i>Kit^V558Δ/+</i> 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. <i>Mol Cancer Ther; 16(9); 1954-66. ©2017 AACR</i>.