Abstract 1350: Direct pharmacological targeting of Gq/11 in uveal melanoma

Uveal (eye) melanoma is a highly aggressive cancer, in which almost half of patients develop distant metastases that are refractory to therapy. In particular, metastatic uveal melanoma has been clinically unresponsive to the immunotherapeutic agents that have shown success in skin tumors, making the need for novel therapeutic approaches to uveal melanoma all the more urgent. Unlike skin melanomas, which are driven by BRAF and NRAS mutations, uveal melanomas arise typically from mutations that result in constitutive activity of the alpha subunit of the heterotrimeric G-protein, Gq, or its paralog G11. The prevalence of constitutively active Gq/11 in uveal melanoma suggests a dependence of these tumors on Gq/11 activity that could be exploited therapeutically. To address this hypothesis, we are using a potent, bioavailable small molecule that binds to and inhibits Gq/11 to target constitutively active Gq/11 in uveal melanoma cells. This inhibitor functions by sequestering wild type or constitutively active Gq/11 in an inactive state. We first used inositol phosphate accumulation assays and confirmed inhibition of both wildtype and constitutively active Gq/11 by the inhibitor in all uveal melanoma cells. We then assayed the affect of Gq/11 inhibition on overall viability of uveal melanoma cells, and found that uveal melanoma cells with mutant Gq/11 were highly sensitive to the small molecule; whereas, uveal melanoma cells with wildtype Gq/11 showed no loss of viability, even at 1000-fold higher concentrations of inhibitor. In Gq-mutant uveal melanoma cells, Gq/11 inhibition caused cell cycle arrest in G1, and dysregulation of several cell cycle regulatory pathways. Inhibitor treatment also caused Gq/11-driven uveal melanoma cells to become more differentiated, as indicated by increased pigmentation, elevated expression of melanin synthesis and melanosome markers, changes in cell morphology and changes in melanocytic versus melanoma gene programs. None of these phenotypic changes were seen in BRAF-driven uveal melanoma cells treated with the Gq/11 inhibitor, demonstrating that the effects of this inhibitor were exquisitely dependent on the constitutively active Gq/11 oncogene. These results establish that Gq/11 is a druggable target in uveal melanoma cells, and show that Gq/11-mutant uveal melanoma cells are exquisitely sensitive to inhibition by small molecule inhibitors. We are currently transitioning these studies to animal models to establish drug efficacy