Linked Life Data

19706776

Source:http://linkedlifedata.com/resource/pubmed/id/19706776

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
17
pubmed:dateCreated
2009-9-2
pubmed:abstractText
Gastrointestinal stromal tumors (GIST) are characterized by activating mutations of KIT or platelet-derived growth factor receptor A (PDGFRA), and treatment with the tyrosine kinase inhibitor imatinib yields responses in the majority of patients. However, most patients develop secondary resistance, which is associated with a dismal prognosis. Histone deacetylase inhibitors (HDACI) have been shown to enhance imatinib activity in imatinib-resistant chronic myelogenous leukemia. Against this background, we explored whether HDACI might provide an alternative therapeutic strategy to KIT/PDGFRA kinase inhibitors in GIST. Inhibition of cell proliferation by HDACI was seen in KIT-positive but not in KIT-negative GIST cell lines, suggesting that HDACI activity is mainly conferred by targeting oncogenic KIT. KIT activity, expression, and activation of downstream pathways were strongly inhibited by several HDACI (SAHA, LBH589, VPA, trichostatin A, and NaButyrate). SAHA and LBH589 induced apoptosis in KIT-positive GIST, and strong synergism with imatinib was observed at low concentrations of SAHA and LBH589. Mechanistically, treatment with HDACI reduced KIT mRNA transcript levels and led to strong acetylation of HSP90, interfering with its activity as KIT chaperone. These results provide preclinical evidence for a disease-specific effect of HDACI in KIT-positive GIST, which could translate into therapeutic activity.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
1538-7445
pubmed:author
pubmed:issnType
Electronic
pubmed:day
1
pubmed:volume
69
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
6941-50
pubmed:dateRevised
2011-5-5
pubmed:meshHeading
pubmed:year
2009
pubmed:articleTitle
Inhibitors of deacetylases suppress oncogenic KIT signaling, acetylate HSP90, and induce apoptosis in gastrointestinal stromal tumors.
pubmed:affiliation
Sarcoma Center, West German Cancer Center, University of Essen, Medical School, Essen, Germany.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't