Author Identifier (ORCID)
Vivian Chua: https://orcid.org/0000-0002-1873-6820
Abstract
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.
Keywords
diacylglycerol kinase, melanoma, NRAS, proliferation, resistance, target, targeted therapy
Document Type
Journal Article
Date of Publication
5-1-2026
Volume
39
Issue
3
PubMed ID
42163799
Publication Title
Pigment Cell & Melanoma Research
Publisher
Wiley
School
Centre for Precision Health / School of Medical and Health Sciences
Funding Information
This work is supported by grants from the National Institutes of Health (NIH)/National Cancer Institute, R01 CA182635 and R01 CA196278, to A.E.A. This work was supported by the NIH/NIGMS T32 Institutional Training Grant T32GM144302. Additional support to A.E.A. was from the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation. The Sidney Kimmel Comprehensive Cancer Center Flow Cytometry, Meta-Omics, Translational Pathology, Laboratory Animal and Bio-Imaging Shared Resources were utilized and supported by the NCI of the NIH under Award Number, P30CA056036. The RPPA studies were performed at the Functional Proteomics Core Facility at The University of Texas MD Anderson Cancer Center, which is supported by a NIH/NCI Cancer Center Support Grant (P30 CA16672).
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Comments
Wilson, H. P., Stefanski, C. D., Caksa, S., Mersky, G. L., Varney, S. D., Haj, J. I., Erkes, D. A., Purwin, T. J., Chua, V., & Aplin, A. E. (2026). Diacylglycerol kinase ETA as a novel target in NRAS mutant melanoma. Pigment Cell & Melanoma Research, 39(3), e70090. https://doi.org/10.1111/pcmr.70090