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F. Mouriaux, A. Calipel, M. Rivoire, A. De La Fouchardière, F. Mascarelli; Effect of Imatinib Mesylate (Glivec) on Tumor-Derived Cells of Metastatic Uveal Melanoma. Invest. Ophthalmol. Vis. Sci. 2008;49(13):60. doi: https://doi.org/.
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Imatinib mesylate is a specific tyrosine kinase inhibitor that targets Bcr-Abl, c-kit, platelet-derived growth factor receptor (PDGFRα, PDGFRβ). In vitro studies have shown that imatinib mesylate was able to decrease the proliferation of primary uveal melanoma cell lines. However a phase II multicentric study of imatinib mesylate was recently conducted in patients with unresectable metastatic uveal melanoma. Unfortunately, no efficiency of imatinib mesylate was observed. The aim of this study is to better understand this clinical resistance.
We used paraffin-embedded biopsies and fresh-frozen samples from hepatic metastases for c-kit and PDGFR expression and immunohistochemistry analysis. We used four hepatic metastatic uveal melanoma derived cell lines (MUM) (OMM1-3, Mum2B, Mum2C and µ2F) to characterize the activity of imatinib mesylate in vitro. Cell viability was assessed by MTT staining. RT-PCR analysis was assessed for the expression of c-kit and PDGFR.
High level of c-kit expression was detected on paraffin-embedded samples and in the fresh-frozen samples. PDGFRα was expressed in 50% of the cases and PDGFRβ was no expressed. Imatinib mesylate was able to decrease the proliferation rates of MUM cell lines in specifics conditions : a strong reduction of cell proliferation was obtained when imatinib mesylate was added to fresh medium, whereas a modest reduction of cell proliferation was obtained when imatinib mesylate was added to medium supplemented with SCF, conditioned medium of MUM, or supplemented with endothelial conditioned medium.
The results suggest that the c-kit molecular pathway may be important in uveal melanoma growth while the PDGFRα and PDGFRβ pathway seemed less implied. No reduction of the c-kit expression was detected in metastatic uveal melanoma tumors. A modest reduction of cell proliferation was observed when, imatinib mesylate is added in MUM conditioned medium, suggesting a that in vivo secreted molecule induce alterations in interaction between the imatinib mesylate with its site of action. These results allowed to better understand the disperancy between previously in vitro studies and the no objective clinical responses of imatinib mesylate in patients with metastatic uveal melanoma.
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