siNRAS and siDGKH knockdown in NRAS mutant melanoma cells

NRAS mutations occur in 10-30% of cutaneous melanomas and are associated with high tumor mutational burden. Mutant NRAS signaling drives aberrant cell growth and proliferation, in part, through the activation of the RAF-MEK-ERK1/2 kinase pathway; however, targeted therapies to this pathway have shown limited effectiveness in melanoma patients. The role of other signaling pathways is poorly characterized. We show that one isoform of diacylglycerol kinase (DGKη), a lipid signaling regulator, is highly expressed in NRAS mutant patient samples. Knockdown of DGKη in NRAS mutant cell lines resulted in significant growth inhibition in vitro, due to decreased cell cycle progression. DGKη was regulated by RAS inhibitors and MEK inhibitors. Transcriptomic data showed downregulation of the estrogen response late signature including decreased CCND1 expression. These data suggest that DGKη mediates cell cycle progression in NRAS mutant melanoma cells and represents a potential therapeutic strategy for these patients.