Blocking Nitrosylation Boosts MEK Inhibitors in Aggressive Melanoma

NRAS mutations, present in 15% to 25% of melanomas, drive aggressive cancer growth that resists current treatments. Identifying new ways to fight this melanoma subtype is crucial, according to Jyoti Srivastava, PhD, senior research scientist at Moffitt Cancer Center. These melanomas often have overactive nitric oxide synthases (NOS), linked to worse outcomes. A study co-led by Srivastava explored how nitrosylation, a modification caused by nitric oxide, affects the cancer-promoting MEK/ERK pathway and a process called immunogenic cell death (ICD) in NRAS-mutant melanomas.

Investigators used lab-grown cells and mouse models to test if blocking both NOS and MEK could be effective. They also mapped overall nitrosylation in these melanomas using advanced techniques and confirmed the nitrosylation of key MEK/ERK regulators and ICD markers. By altering specific protein sites, researchers pinpointed where nitrosylation occurs on MEK and ERK. Additionally, they examined how nitrosylation impacts molecules that regulate ICD and antimelanoma immunity using cell-based tests and mouse models that can mount an immune response. They further investigated the immune role of nitrosylation by studying interactions between dendritic cells and CD8+ T-cells.

Blocking nitrosylation made the melanoma cells more sensitive to MEK inhibitors. Investigators found a strong link between reduced nitrosylation of MEK/ERK pathway proteins and similar changes in danger signals (DAMPs) that trigger ICD. They also located specific nitrosylation sites on MEK and ERK that are vital for melanoma cell growth.

Interestingly, melanoma cells that became resistant to MEK inhibitors showed increased nitrosylation and activation of cancer-promoting proteins, which was reversed by blocking NOS. In mice with NRAS-mutant melanoma, inhibiting both nitrosylation and MEK significantly slowed tumor growth. Both cell and animal models showed that blocking nitrosylation led to the release of ICD-related DAMPs, such as calreticulin, phospho-eIF2α, and HMGB1. This release activated dendritic cells, leading to the growth and activation of cancer-fighting CD8+ T-cells within the tumor.

In an interview with Targeted Oncology^TM, Srivastava discusses how nitrosylation fuels the MEK-ERK pathway and suppresses the body's antimelanoma defenses, promoting tumor progression and resistance to MEK inhibitors. Blocking nitrosylation not only improves how well MEK inhibitors work but also triggers ICD. Further research into the detailed mechanisms will reveal new treatment targets for this currently difficult-to-treat NRAS-mutant melanoma.