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

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

  • Shan Zeng - , Memorial Sloan-Kettering Cancer Center (Autor:in)
  • Adrian M Seifert - , Klinik und Poliklinik für Viszeral- Thorax- und Gefäßchirurgie, Nationales Centrum für Tumorerkrankungen Dresden, Memorial Sloan-Kettering Cancer Center (Autor:in)
  • Jennifer Q Zhang - , Memorial Sloan-Kettering Cancer Center (Autor:in)
  • Michael J Cavnar - , Memorial Sloan-Kettering Cancer Center (Autor:in)
  • Teresa S Kim - , Memorial Sloan-Kettering Cancer Center (Autor:in)
  • Vinod P Balachandran - , Memorial Sloan-Kettering Cancer Center (Autor:in)
  • Juan A Santamaria-Barria - , Memorial Sloan-Kettering Cancer Center (Autor:in)
  • Noah A Cohen - , Memorial Sloan-Kettering Cancer Center (Autor:in)
  • Michael J Beckman - , Memorial Sloan-Kettering Cancer Center (Autor:in)
  • Benjamin D Medina - , Memorial Sloan-Kettering Cancer Center (Autor:in)
  • Ferdinand Rossi - , Memorial Sloan-Kettering Cancer Center (Autor:in)
  • Megan H Crawley - , Memorial Sloan-Kettering Cancer Center (Autor:in)
  • Jennifer K Loo - , Memorial Sloan-Kettering Cancer Center (Autor:in)
  • Joanna H Maltbaek - , Memorial Sloan-Kettering Cancer Center (Autor:in)
  • Peter Besmer - , Memorial Sloan-Kettering Cancer Center (Autor:in)
  • Cristina R Antonescu - , Memorial Sloan-Kettering Cancer Center (Autor:in)
  • Ronald P DeMatteo - , Memorial Sloan-Kettering Cancer Center (Autor:in)

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. Mol Cancer Ther; 16(9); 1954-66. ©2017 AACR.

Details

OriginalspracheEnglisch
Seiten (von - bis)1954-1966
Seitenumfang13
FachzeitschriftMolecular cancer therapeutics
Jahrgang16
Ausgabenummer9
PublikationsstatusVeröffentlicht - Sept. 2017
Peer-Review-StatusJa

Externe IDs

PubMedCentral PMC5587376
Scopus 85029208898
ORCID /0000-0002-5329-3164/work/147141103

Schlagworte

Ziele für nachhaltige Entwicklung

Schlagwörter

  • Animals, Antineoplastic Agents/pharmacology, Cell Line, Tumor, Disease Models, Animal, Gastrointestinal Stromal Tumors/drug therapy, Humans, Imatinib Mesylate/pharmacology, Intercellular Signaling Peptides and Proteins/metabolism, Mice, Mice, Transgenic, Molecular Targeted Therapy, Neoplasm Grading, Neoplasm Staging, Ubiquitin-Protein Ligases/metabolism, Wnt Signaling Pathway/drug effects, Wnt3A Protein/metabolism, Xenograft Model Antitumor Assays, beta Catenin/metabolism