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.
|Number of pages||13|
|Journal||Molecular Cancer Therapeutics|
|State||Published - Sep 2017|
Bibliographical noteFunding Information:
This work was supported by NIH grants R01 CA102613 and T32 CA09501, Betsy Levine-Brown and Marc Brown, David and Monica Gorin, and the Stephanie and Fred Shuman through the Windmill Lane Foundation (to R.P. DeMatteo); GIST Cancer Research Fund (to R.P. DeMatteo and C.R. Antonescu); F32 CA162721 and the Claude E. Welch Fellowship from the Massachusetts General Hospital (to T.S. Kim); F32 CA186534 (to J.Q. Zhang); and P50 CA140146-01 (to C.R. Antonescu).
ASJC Scopus subject areas
- Cancer Research