Expression, mutational analysis and in vitro response of imatinib mesylate and nilotinib target genes in ovarian granulosa cell tumors.
OBJECTIVE
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.
Chu
Simon
S
Prince Henry's Institute of Medical Research, Clayton, Victoria, Australia.
Alexiadis
Maria
M
Fuller
Peter J
PJ
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D005260:Female; D020869:Gene Expression Profiling; D016236:Genes, fms; D006106:Granulosa Cell Tumor / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology*; D016315:Proto-Oncogene Proteins c-abl / Q000096:biosynthesis / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000096:biosynthesis / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000096:biosynthesis / Q000235:genetics; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000970:Antineoplastic Agents; D001549:Benzamides; D008565:Membrane Proteins; D010879:Piperazines; D011743:Pyrimidines; D012333:RNA, Messenger; C084881:flt3 ligand protein; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta; D016315:Proto-Oncogene Proteins c-abl; C498826:nilotinib