Targeting Oncogenic Gα(q/11) in Uveal Melanoma

SIMPLE SUMMARY: Uveal melanoma is a deadly form of eye cancer with a high rate of metastasis. Once metastasis occurs, patients are often left with a short survival time, since there is no FDA standard of care for the metastatic disease. Uveal melanoma develops from mutations mainly in proteins involved in the G(q/11) signaling pathway, which drives pathogenesis. This review article aims to summarize pre-clinical and clinical studies that have attempted to understand and treat the disease by inhibiting the G(q/11) signaling pathway. We discuss the limited success of treatments focused on downstream targets of the G(q/11) pathway and evaluate the effectiveness and feasibility of treating the disease by directly inhibiting G(q/11). ABSTRACT: 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 GNAQ and GNA11 genes being found in over 90% of patients. These genes encode the alpha subunits of the hetetrotrimeric G proteins, G(q) and G(11), 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(q) and G(11) in mouse models. While selective targeting of G(q) and G(11) provides a potential therapeutic strategy to treat uveal melanoma, it is evident that improved inhibitors and methods of delivery are needed.