Abstract 2706: Crizotinib, a selective c-Met inhibitor, prevents metastasis to the liver and lungs in a primary uveal melanoma mouse model.

Abstract

Abstract Uveal melanoma is the most common primary intraocular malignant tumor in adults. About half of patients with uveal melanoma will develop metastatic disease to the liver and the lung. These tumors are characterized by mutations in G-proteins (GNAQ and GNA11) and also the over-expression of c-Met. Crizotinib is a selective inhibitor for c-Met as well as anaplastic lymphoma kinase (ALK). We found that crizotinib inhibited cell proliferation of uveal melanoma cell lines in a dose dependent manner with an IC50 in the range of 0.75 μM to 2 μM. Phospho-c-Met was inhibited by crizotinib starting at 10 nM with inhibition of downstream signaling including p-ERK1/2, p-AKT and p-STAT. In our xenograft model there was only a modest inhibition of tumor growth after treatment with doses of ≥ 50 mg/kg crizotinib. As crizotinib also prevented cell migration regardless of G-protein status, we established a primary metastatic uveal mouse model in which we created a GFP-luciferase expressing uveal melanoma cell line that developed liver and lung metastases 6 weeks after primary implantation into the eye. At a dose of 50 mg/kg daily, starting 4 weeks after primary implantation, there was a dramatic reduction in the liver and lungs metastases when compared to untreated controls. These results indicate that the inhibition of c-Met alone may be sufficient to prevent metastasis of uveal melanoma and suggest there may be a potential for using crizotinib as an adjuvant therapy in uveal melanoma. Citation Format: Oliver Surriga, Rajasekhar Vinagolu, Grazia Ambrosini, Gary Schwartz. Crizotinib, a selective c-Met inhibitor, prevents metastasis to the liver and lungs in a primary uveal melanoma mouse model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2706. doi:10.1158/1538-7445.AM2013-2706