Diacylglycerol Kinase Eta as a Novel Target in NRAS Mutant Melanoma

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 activation of the RAF-MEK-ERK1/2 kinase pathway; however, targeted therapies to this pathway have limited effectiveness in patients with NRAS mutant melanoma. The role of other targetable signaling pathways in NRAS mutant melanoma is poorly characterized. Here, we demonstrated that one isoform of diacylglycerol kinase, diacylglycerol kinase eta (DGKη), a lipid signaling regulator, was highly expressed in NRAS mutant melanoma patient samples. Knockdown of DGKH in NRAS mutant melanoma cell lines resulted in significant growth inhibition in vitro. Transcriptomic data indicated downregulation of the estrogen response late signature, including decreased CCND1 (cyclin D1) expression following DGKH knockdown. Cell growth inhibition and decreased cyclin D1 expression correlated to an inhibition of cell cycle after DGKH knockdown. These data suggest that DGKη mediates cell cycle progression in NRAS mutant melanoma cells and represents a potential therapeutic target for these patients.