Abstract 3587: XL184: c-Met inhibition is effective in a mouse xenograft model of metastatic uveal melanoma

Oncogenic mutation of GNAQ is an early event in uveal melanoma development. Identification of critical downstream effectors of GNAQ could allow for targeted therapy of this deadly form of melanoma. We identified c-Met upregulation as a downstream effect of GNAQ Q209L mutation by analyzing expression changes in immortalized mouse melanocytes transduced with GNAQ Q209L. By Western blot, we established that c-Met protein expression is increased in human uveal melanoma cell lines that harbor a GNAQ activating mutation compared to lines with wild-type GNAQ. XL184 is a small-molecule tyrosine kinase inhibitor that has activity against c-Met. In vitro assays of XL184 demonstrated preferential activity against human uveal melanoma cell lines (OMM1.3 and Mel202) with GNAQ activating mutations. Intravenous injection of 1×106 OMM1.3 cells into immunocompromised NSG mice results in the development of multiple liver tumor nodules after 6-8 weeks, recapitulating liver tropism (over 80% of patients with metastatic uveal melanoma have liver metastases). We treated mice starting four weeks after OMM1.3 intravenous injection with XL184. After four weeks of treatment, the treated mice demonstrated decreased liver tumor size with central tumor necrosis on histologic examination. The activity of XL184 is likely through its inhibition of c-Met signaling as we found little expression of the other targets of XL184 in OMM1.3. In conclusion, XL184 demonstrates activity in a mouse xenograft model of metastatic uveal melanoma, and has potential to be active against hepatic metastases of uveal melanoma, the major cause of mortality in this rare cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3587. doi:10.1158/1538-7445.AM2011-3587