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Abstract
Mutations in GNAQ and GNA11 (GNAQ/11) occur in a mutually exclusive pattern and are found in less than 2% of all cancer types. Uniquely, GNAQ/11 driver mutations are found in more than 90% of uveal melanoma, a rare malignancy of pigment-producing melanocytes that are located along the choroid, ciliary body, or iris of the eye. GNAQ/11 encode for Gαq proteins that are essential for G-protein coupled receptor signaling. In uveal melanoma, GNAQ/11 mutations lead to constitutive downstream activation of oncogenic pathways, including mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K), and yes-associated protein (YAP) signaling. Although these oncogenic pathways have been shown to contribute to uveal melanoma growth and survival, clinical trials utilizing targeted therapy of actionable targets downstream of GNAQ/11 have failed to demonstrate any survival benefit for metastatic uveal melanoma patients. In fact, in stark contrast to metastatic melanoma of cutaneous origin, there are currently no effective treatments available for metastatic uveal melanoma. Thus, identifying effective treatment strategies for this particular malignancy is an urgent and unmet clinical need. Recent preclinical studies have focused on combination approaches, mainly using inhibitors of MEK1/2, a serine/threonine kinase in the MAPK pathway. Specifically, I reveal a novel treatment approach combining MEK1/2 inhibition with chloroquine, an antimalarial, that delays tumor growth in preclinical models of GNAQ/11-mutant melanoma.
