Promising strategy could enhance treatment of melanoma subset

In a development that could alter the therapeutic landscape for a challenging subset of melanoma, scientists at the Moffitt Cancer Center in Tampa, Fla. have identified a novel approach to sensitize NRAS-mutant melanoma to treatment. Their findings in a pre-clinical model, published in Cancer Research, suggest that inhibiting nitrosylation may improve the efficacy of existing therapies for this aggressive cancer subtype.

NRAS-mutant melanoma accounts for approximately 25% of all melanoma cases and is characterized by resistance to many current treatment modalities, including immunotherapy and targeted agents. The prognosis for patients with this mutation remains poor, underscoring the need for innovative therapeutic strategies.

The Moffitt team’s research focused on the interplay between nitrosylation and the MEK-ERK signalling pathway, which is central to tumour proliferation. Laboratory and animal model experiments demonstrated that blocking nitrosylation made NRAS-mutant melanoma cells more susceptible to MEK inhibitors. The combination of nitrosylation inhibitors and MEK inhibitors resulted in significantly reduced tumour growth.

“Our research shows that nitrosylation helps cancer cells survive treatment and evade the immune system,” said Sanjay Premi, PhD, assistant member in the Tumor Microenvironment and Metastasis Department at Moffitt and co-lead author of the study in a press release. “When we block it, we weaken the cancer’s defences, kill the cancer cells and help the immune system attack the tumour.”

Sanjay Premi, PhD. Photo courtesy Moffitt Cancer Center

Further investigation showed that nitrosylation inhibition induced immunogenic cell death in tumour cells. This process prompts the release of distress signals, which in turn attract immune effector cells, including CD8-positive T cells and dendritic cells, to the tumour microenvironment.

“This approach not only restricts the tumour growth but also enhances the body’s own anti-cancer immune response,” said Jyoti Srivastava, PhD, co-lead author and senior research scientist at Moffitt. “It could lead to more durable responses for patients who currently have limited options.”

Current treatments for NRAS-mutant melanoma, such as MEK inhibitors, have shown only modest clinical benefit, with limited improvements in progression-free survival and no significant impact on overall survival. The addition of nitrosylation inhibition, as demonstrated in preclinical models, offers a potential new avenue for combination therapy.

The study’s authors advocate for further clinical investigation of nitrosylation inhibitors in combination with MEK inhibitors, not only for melanoma but potentially for other malignancies characterized by similar resistance mechanisms.