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Updated: Apr 16, 2026
A 3D Organotypic Melanoma Spheroid Skin Model
Published on: May 18, 2018
Treatment of NRAS-mutant melanoma
Douglas B Johnson1, Igor Puzanov
1Department of Medicine, Division of Hematology/Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 777 Preston Research Building, 2220 Pierce Avenue, Nashville, TN, 37232, USA, douglas.b.johnson@vanderbilt.edu.
Abstract:
NRAS mutations in codons 12, 13, and 61 arise in 15-20 % of all melanomas. These alterations have been associated with aggressive clinical behavior and a poor prognosis. Until recently, there has been a paucity of promising genetically targeted therapy approaches for NRAS-mutant melanoma (and RAS-mutant malignancies in general). MEK inhibitors, particularly binimetinib, have shown activity in this cohort. Based on pre-clinical and early clinical studies, combining MEK inhibitors with agents inhibiting the cell cycling and the PI3K-AKT pathway appears to provide additional benefit. In particular, a strategy of MEK inhibition and CDK4/6 inhibition is likely to be a viable treatment option in the future, and is the most promising genetically targeted treatment strategy for NRAS-mutant melanoma developed to date. In addition, immune-based therapies have shown increasing activity in advanced melanoma and may be particularly effective in those with NRAS mutations. Combination strategies of immune and targeted therapies may also play a role in the future although clinical trials testing these approaches are in early stages.
Insights
NRAS mutations in melanoma are linked to poor prognosis, but new targeted therapies like MEK inhibitors show promise. Combining MEK inhibitors with cell cycle or PI3K-AKT pathway agents offers a viable future treatment strategy.
Area of Science:
- Oncology
- Genetics
- Dermatology
Background:
- NRAS mutations (codons 12, 13, 61) occur in 15-20% of melanomas.
- These mutations are associated with aggressive disease and poor prognosis.
- Limited targeted therapy options existed for NRAS-mutant melanoma previously.
Purpose of the Study:
- To review current and emerging targeted therapies for NRAS-mutant melanoma.
- To explore the potential of combination strategies involving MEK inhibitors.
- To discuss the role of immunotherapy in NRAS-mutant melanoma.
Main Methods:
- Review of pre-clinical and early clinical studies on NRAS-mutant melanoma treatments.
- Analysis of MEK inhibitor efficacy, particularly binimetinib.
- Evaluation of combination therapies targeting cell cycling, PI3K-AKT pathway, and immune responses.
Main Results:
- MEK inhibitors demonstrate activity in NRAS-mutant melanoma.
- Combining MEK inhibitors with cell cycle (e.g., CDK4/6) or PI3K-AKT pathway inhibitors shows potential benefit.
- Immunotherapies are increasingly active in advanced melanoma and may benefit NRAS-mutant cases.
Conclusions:
- MEK and CDK4/6 inhibition represents a promising targeted strategy for NRAS-mutant melanoma.
- Combination strategies involving targeted and immune therapies warrant further investigation.
- Future treatment of NRAS-mutant melanoma will likely involve sophisticated combination approaches.
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