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Ref Type Journal Article
PMID (28611108)
Authors Zeng S, Seifert AM, Zhang JQ, Cavnar MJ, Kim TS, Balachandran VP, Santamaria-Barria JA, Cohen NA, Beckman MJ, Medina BD, Rossi F, Crawley MH, Loo JK, Maltbaek JH, Besmer P, Antonescu CR, DeMatteo RP
Title Wnt/β-catenin Signaling Contributes to Tumor Malignancy and Is Targetable in Gastrointestinal Stromal Tumor.
Journal Molecular cancer therapeutics
Vol 16
Issue 9
Date 2017 09
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown gastrointestinal stromal tumor not applicable PKF118-310 Preclinical - Cell line xenograft Actionable In a preclinical study, PKF118-310 decreased viability of gastrointestinal stromal tumor (GIST) cell lines in culture, and reduced tumor growth in xenograft models (PMID: 28611108). 28611108
KIT V560del gastrointestinal stromal tumor sensitive G007-LK + Imatinib Preclinical Actionable In a preclinical study, the combination of G007-LK and Gleevec (imatinib) demonstrated increased anti-tumor activity compared to either agent alone in a mouse model of gastrointestinal stromal tumor expressing Kit V558del (corresponding to human V560del) (PMID: 28611108). 28611108
KIT exon11 gastrointestinal stromal tumor sensitive Imatinib + XAV939 Preclinical - Cell culture Actionable In a preclinical study, treatment with the combination of XAV939 and Gleevec (imatinib) resulted in decreased viability of gastrointestinal stromal tumor (GIST) cell lines harboring KIT exon 11 mutations compared to Gleevec (imatinib) alone, in culture (PMID: 28611108). 28611108
KIT exon11 gastrointestinal stromal tumor sensitive Imatinib + PKF118-310 Preclinical - Cell culture Actionable In a preclinical study, treatment with the combination of PKF118-310 and Gleevec (imatinib) resulted in decreased viability of gastrointestinal stromal tumor (GIST) cell lines harboring KIT exon 11 mutations compared to Gleevec (imatinib) alone, in culture (PMID: 28611108). 28611108
Unknown unknown gastrointestinal stromal tumor not applicable G007-LK Preclinical Actionable In a preclinical study, G007-LK demonstrated anti-tumor activity in a mouse model of gastrointestinal stromal tumor expressing Kit V558del (corresponding to human V559del) (PMID: 28611108). 28611108