Overcoming Drug Resistance in NRAS-Mutant Melanoma via Epigenetic Therapy

Melanoma is an aggressive type of skin cancer known for its rapid spread and frequent resistance to current treatments. Many advanced melanomas carry genetic mutations in the NRAS gene, making them particularly challenging to treat effectively. Recently, new medications known as multi-RAS inhibitors have shown promising initial results; however, melanoma cells quickly develop resistance, diminishing the effectiveness of these therapies. Our research identified that melanoma cells become drug-resistant through changes in gene expression levels—a process called epigenetic regulation.

In our studies, we discovered that drugs known as histone deacetylase inhibitors (HDACi), which influence how genes are activated or silenced, can help melanoma cells overcome resistance and regain sensitivity to treatments. Notably, even brief exposure to HDACi drugs can produce lasting effects, maintaining the reversal of drug resistance long after treatment ends. Our ongoing work aims to rigorously evaluate this innovative approach through detailed laboratory models and animal studies. By understanding precisely how HDACi drugs reverse melanoma resistance and by determining the best ways to use these drugs clinically, we aim to develop safer, more durable, and effective therapies for patients suffering from difficult-to-treat NRAS-mutant melanoma.