RGD Reference Report - Expression, mutational analysis and in vitro response of imatinib mesylate and nilotinib target genes in ovarian granulosa cell tumors. - Rat Genome Database

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Expression, mutational analysis and in vitro response of imatinib mesylate and nilotinib target genes in ovarian granulosa cell tumors.

Authors: Chu, S  Alexiadis, M  Fuller, PJ 
Citation: Chu S, etal., Gynecol Oncol. 2008 Jan;108(1):182-90. Epub 2007 Oct 29.
RGD ID: 2302173
Pubmed: PMID:18028988   (View Abstract at PubMed)
DOI: DOI:10.1016/j.ygyno.2007.09.017   (Journal Full-text)

OBJECTIVES: Granulosa cell tumors of the ovary (GCT) represent approximately 5% of malignant ovarian tumors. Surgery remains the primary modality of therapy and treatment options for advanced disease are limited. The molecular pathogenesis of GCT is not known but is likely to involve activation of tyrosine kinase-mediated cell signaling pathways. A recent case report of a patient with advanced recurrent GCT responding to the tyrosine kinase inhibitor, imatinib mesylate prompted us to explore a role for these therapies in GCT. METHODS: The expression of the imatinib-sensitive tyrosine kinases, c-kit, c-Abl, PDGFR-alpha and PDGFR-beta, was determined using RT-PCR in a panel of GCT. Activating mutations of c-kit and PDGFR-alpha were also sought. The functional response was examined in two human-derived GCT cell lines. RESULTS: All four kinases were expressed but at levels lower than those observed in pre-menopausal ovarian samples. Mutations in c-kit and PDGFR-alpha were not found. Both cell lines responded to imatinib and to the second generation, tyrosine kinase inhibitor, nilotinib, with dose-dependent decreases in cell proliferation and viability. These responses paralleled the imatinib-sensitive, K562 cell line but at approximately 240- and approximately 1000-fold higher concentrations of imatinib and nilotinib, respectively. CONCLUSIONS: Our study suggests that human GCT, in general, are unlikely to respond to imatinib or nilotinib therapy. The response of the cell lines at high concentrations implies an "off-target" effect, which suggests that a tyrosine kinase inhibitor, of appropriate specificity, may represent a therapeutic option in GCT.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
granulosa cell tumor  IEP 2302173mRNA:decreased expression:ovaryRGD 
granulosa cell tumor  ISOKIT (Homo sapiens)2302173; 2302173mRNA:decreased expression:ovaryRGD 

Objects Annotated

Genes (Rattus norvegicus)
Kit  (KIT proto-oncogene receptor tyrosine kinase)

Genes (Mus musculus)
Kit  (KIT proto-oncogene receptor tyrosine kinase)

Genes (Homo sapiens)
KIT  (KIT proto-oncogene, receptor tyrosine kinase)


Additional Information