Targeting Oncogenic Gα in Uveal Melanoma.

Uveal melanoma is the most common intraocular cancer in adults and arises from the transformation of melanocytes in the uveal tract. While treatment of the primary tumor is often effective, 36-50% of patients develop metastatic disease primarily to the liver. While various strategies have been used to treat the metastatic disease, there remain no effective treatments that improve survival. Significant insight has been gained into the pathways that are altered in uveal melanoma, with mutually exclusive activating mutations in the and genes being found in over 90% of patients. These genes encode the alpha subunits of the hetetrotrimeric G proteins, G and G, and mutations result in activation of several important signaling pathways, including phospholipase C and activation of the transcription factor YAP. In this review, we discuss current efforts to target various signaling pathways in the treatment of uveal melanoma including recent efforts to target G and G in mouse models. While selective targeting of G and G provides a potential therapeutic strategy to treat uveal melanoma, it is evident that improved inhibitors and methods of delivery are needed.