PURPOSE: Uveal melanoma is the most common primary tumor of the eye in adults. There is no standard adjuvant treatment to prevent metastases and no effective therapy in the metastatic setting. Relevant models of uveal melanoma are necessary to preclinical assessment of drugs activity. The goal of this study was to develop cell lines recapitulating the genetic landscape of uveal melanoma and identify therapeutic approaches for treatment using in vitro and in vivo models.
EXPERIMENTAL DESIGN: Tumors samples from patients or patient-derived xenografts were put into culture.The cell lines obtained were characterized for chromosomal alterations and reported recurrent mutations. They were tested for sensitivity to a selected panel of drugs including the mTOR inhibitor Everolimus. We assessed mTOR signaling activation in the cell lines and evaluated the effect of Everolimus in patient-derived xenografts.
RESULTS: We established seven uveal melanoma cell lines. All display either GNAQ or GNA11 activating mutations, three harbor BAP1 mutations, and one an EIF1AX mutation. No cell line exhibits SF3B1 mutations. mTOR pathway was shown to be activated in these cells. Everolimus reduced viability of the cell lines and significantly delayed in vivo tumor growth of 4 patient-derived xenografts.
CONCLUSIONS: Our established panel of uveal melanoma cell lines represents a relevant preclinical tool for the study of this disease. Our in vitro and in vivo data suggest that mTOR inhibition with Everolimus, most probably in combination with other agents, may be considered as a therapeutic option for the management of uveal melanoma.
Citation Format: Nabil Amirouchene-Angelozzi, Fariba Nemati, David Gentien, May-Linda Lepage, André Nicolas, Jordan Madic, Amaury Dumont, Guillaume Carita, Jaques Camonis, Laurence Desjardins, Nathalie Cassoux, Sophie Piperno-Neumann, Pascale Mariani, Xavier Sastre, Didier Decaudin, Sergio Roman-Roman. Establishment of novel cell lines recapitulating the genetic landscape of uveal melanoma and preclinical validation of mTOR as a therapeutic target. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3915. doi:10.1158/1538-7445.AM2014-3915