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Ref Type Journal Article
PMID (26936919)
Authors Wang HC, Li TY, Chao YJ, Hou YC, Hsueh YS, Hsu KH, Shan YS
Title KIT Exon 11 Codons 557-558 Deletion Mutation Promotes Liver Metastasis Through the CXCL12/CXCR4 Axis in Gastrointestinal Stromal Tumors.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 22
Issue 14
Date 2016 Jul 15
URL
Abstract Text KIT mutations, the most prevalent genetic event in gastrointestinal stromal tumors (GIST), are associated with malignant features and poor prognosis. Aggressive GISTs possess a high propensity to spread to the liver. This study aimed to explore the role of KIT mutations in GIST liver metastasis.A total of 170 GISTs were used to determine the association between KIT mutations and liver metastasis. Immunohistochemistry was performed to assess the correlation of KIT mutations with CXCR4 and ETV1 expression. Genetic and pharmacologic methods were used to study the regulation of CXCR4 and ETV1 by KIT mutations.Codons 557 and 558 in KIT exon 11 were deletion hot spots in GISTs. KIT exon 11 deletions involving codons 557-558 were highly associated with liver metastasis. Overexpression of mutant KIT with exon 11 codons 557-558 deletion (KIT Δ557-558) increased GIST cell motility and liver metastasis. Mechanistically, overexpression of KIT Δ557-558 in GIST cells increased ETV1 and CXCR4 expression. CXCR4 knockdown counteracted KIT Δ557-558-mediated cell migration. Moreover, KIT Δ557-558-induced CXCR4 expression could be abolished by silencing ETV1. The chromatin immunoprecipitation assay showed that ETV1 directly bound to the CXCR4 promoter. After ERK inhibitor PD325901 treatment, the upregulation of ETV1 by KIT Δ557-558 was prevented. In addition, KIT exon 11 codons 557-558 deletion enhanced CXCL12-mediated GIST cell migration and invasion.KIT exon 11 557-558 deletion upregulates CXCR4 through increased binding of ETV1 to the CXCR4 promoter in GIST cells, which thus promotes liver metastasis. These findings highlighted the potential therapeutic targets for metastatic GISTs. Clin Cancer Res; 22(14); 3477-87. ©2016 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
KIT W557_K558del deletion gain of function KIT W557_K558del results in the deletion of 2 amino acids in the juxtamembrane domain (exon 11) of the Kit protein from amino acids 557 to 558 (PMID: 12918066). W557_K558del results in constitutive activation of Kit and increased Erk phosphorylation, and leads to increased invasiveness and expression of ETV1 in cell culture (PMID: 25239608, PMID: 26936919).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KIT W557_K558del gastrointestinal stromal tumor sensitive PD-0325901 Preclinical - Cell culture Actionable In a preclinical study, PD-0325901 treatment inhibited Erk phosphorylation and decreased expression of ETV1 and CXCR4 in gastrointestinal stromal tumor cells harboring KIT W557_K558del (PMID: 26936919). 26936919