Wnt/β-catenin signaling contributes to tumor malignancy and is targetable in gastrointestinal stromal tumor Journal Article
| Authors: | Zeng, S.; Seifert, A. M.; Zhang, J. Q.; Cavnar, M. J.; Kim, T. S.; Balachandran, V. P.; Santamaria-Barria, J. A.; Cohen, N. A.; Beckman, M. J.; Medina, B. D.; Rossi, F.; Crawley, M. H.; Loo, J. K.; Maltbaek, J. H.; Besmer, P.; Antonescu, C. R.; DeMatteo, R. P. |
| Article Title: | 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 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. ©2017 AACR. |
| Journal Title: | Molecular Cancer Therapeutics |
| Volume: | 16 |
| Issue: | 9 |
| ISSN: | 1535-7163 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2017-09-01 |
| Start Page: | 1954 |
| End Page: | 1966 |
| Language: | English |
| DOI: | 10.1158/1535-7163.mct-17-0139 |
| PROVIDER: | scopus |
| PMCID: | PMC5587376 |
| PUBMED: | 28611108 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 October 2017 -- Source: Scopus |
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