Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	16	9	2017 09	1954-1966	Mol Cancer Ther

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
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