Wnt/β-catenin signaling contributes to tumor malignancy and is targetable in gastrointestinal stromal tumor

Shan Zeng, Adrian M. Seifert, Jennifer Q. Zhang, Michael J. Cavnar, Teresa S. Kim, Vinod P. Balachandran, Juan A. Santamaria-Barria, Noah A. Cohen, Michael J. Beckman, Benjamin D. Medina, Ferdinand Rossi, Megan H. Crawley, Jennifer K. Loo, Joanna H. Maltbaek, Peter Besmer, Cristina R. Antonescu, Ronald P. DeMatteo

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1954-1966
Number of pages13
JournalMolecular cancer therapeutics
Volume16
Issue number9
DOIs
StatePublished - Sep 2017
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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