Targeting Nitrosylation: A New Strategy for NRAS-Mutant Melanoma
NRAS mutations, present in 15% to 25% of melanomas, drive aggressive cancer growth that resists current treatments. It is crucial to find new ways to fight this, according to Sanjay Premi, PhD, assistant professor in the Department of Tumor Microenvironment and Metastasis Moffitt Cancer Center. These melanomas often have overactive nitric oxide synthases (NOS), linked to worse outcomes. A study co-led by Premiexplored how nitrosylation, a modification caused by nitric oxide, affects the cancer-promoting MEK/ERK pathway and a process called immunogenic cell death in NRAS-mutant melanomas.
Investigators identified that nitrosylation is responsible for inducing drug resistance in these melanomas. They were able to reverse that effect in vitro using cell culture systems as well as mouse models. Additionally, they found out that not only drug resistance, but this particular modification was making the melanomas resistant to immunotherapies and immune environment in solid tumors. By blocking nitrosylation, investigators were able to desensitize these melanomas to the same drugs against which they were not responding earlier.
Premi added that researchers were also able to reactivate the immune system so that the immune cells could recognize the tumor cells and start getting rid of them.
"We have simply started scratching the surface in this field, especially nitrosylation. We have also identified a couple of proteins and their specific sites where these modifications are, so that in future, if you want to have some targeted molecules against these particular sites or particular proteins, we will be able to do that as well," said Premi in an interview with Targeted OncologyTM.
"There are hundreds of other proteins which we have identified, and we have characterized the function of only 2, and as it is expected with any cancer where multiple things are going wrong in several different directions. You cannot use simply 1 drug to cure cancer. So we think, and we hope that nitrosylation blocking will be a strategy which will target several different pathways simultaneously," added Premi.
