Research in practice : therapeutic targeting of oncogenic GNAQ mutations in uveal melanoma

Abstract

Uveal melanoma is the most common form of eye cancer and has a poor prognosis. Although the primary tumor in most cases is treated effectively by local surgery or radiotherapy, over 50 % of patients develop systemic metastasis, especially in the liver. In contrast to cutaneous melanoma, there is no standard-of-care treatment for metastasized uveal melanoma. Recently, oncogenic driver mutations in GNAQ or GNA11 were identified in about 85 % of uveal melanomas, which lead to constitutively active signaling in the Gαq/11 pathway and its downstream effectors. Direct targeting of deregulated Gαq/11 signaling might therefore be a therapeutic option for patients with uveal melanoma. In our study we identified the cyclic depsipeptide FR-900359, which is isolated from the evergreen plant Ardisia crenata as an effective inhibitor of constitutively active Gαq/11 proteins and their downstream targets. Although our data are preliminary, they might contribute to a future treatment option for patients with metastasized uveal melanoma.