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A. B. Daniels, C. R. Antonescu, K. J. Busam, D. H. Abramson; Lack of Deregulation of Either c-Kit or PDGFR in Uveal Melanoma via Mutation or Amplification. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5441.
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Uveal melanoma is almost universally fatal once metastatic and chemotherapeutic regimens thus far have been disappointing. Recent evidence has indicated that uveal melanomas may express the receptor c-kit, which has led to the hope that the c-kit targeted tyrosine kinase inhibitor, imatinib (Gleevec), could revolutionize therapy the way it has for other diseases. However, imatinib appears to only be effective when a tumor is dependent on c-kit for proliferation, and this is associated with mutation or gene amplification. We aimed to determine if either of these is present in uveal melanoma. Since imatinib can also be used to target the Platelet-Derived Growth Factor Receptor (PDGFR), we likewise examined this receptor for mutations or gene amplifications as well.
Ten primary uveal melanomas were immuno-stained with c-kit antibody to assess c-kit expression. Those that were c-kit immuno-reactive were subjected to direct sequencing for mutations. Gene amplification or duplication was assessed using fluorescence in situ hybridization (FISH). The PDGFR gene was likewise directly sequenced to analyze for the presence of mutations, and FISH analysis was used to determine gene copy number.
5/10 (50%) of tumors expressed c-kit. There were no mutations found in any of the exons commonly implicated in c-kit activation, nor were there any gene amplifications by FISH analysis. The PDGFR gene likewise did not show any mutations throughout the exons analyzed, nor were there gene amplifications.
While c-kit might make an attractive target for the treatment of uveal melanoma based on the availability of a targeted biologic agent, this is reliant on c-kit- or PDGFR-dependent proliferation via deregulated and constitutively activated c-kit or PDGFR pathways. We found no evidence that either c-kit or PDGFR is deregulated via mutation or amplification in primary uveal melanomas.
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