A new study has identified a biological pathway that could explain why many patients with advanced melanoma, a deadly form of skin cancer, do not respond to current treatments. Published in *Cancer Research* on June 10, the study sheds light on potential new treatment options for patients whose melanoma fails to respond to immune checkpoint inhibitors, a commonly used immunotherapy.
The research, led by NYU Langone Health and its Perlmutter Cancer Center, focuses on melanoma patients with mutations in the neurofibromin 1 (NF1) gene. These mutations, which affect the molecular structure of the gene, are one of several genetic factors linked to melanoma. An estimated 27% of melanoma patients carry NF1 mutations. While immunotherapy has proven effective for many, it does not work for over half of patients with NF1-mutant melanoma.
Milad Ibrahim, PhD, the lead investigator of the study, emphasized the urgent need for alternative treatments for these patients, particularly those who do not respond to immunotherapy and have limited options. Ibrahim is a postdoctoral fellow at the NYU Grossman School of Medicine.
To explore why these patients were resistant to treatment, researchers analyzed tumor samples from 30 melanoma patients who did not respond to immunotherapy. NF1 mutations were present in 40% of these cases. Molecular testing revealed that melanoma cells with NF1 mutations showed heightened activity in a signaling pathway centered around the epidermal growth factor receptor (EGFR). This pathway has long been associated with tumor growth and poor survival in various cancers, including melanoma. The study found that these mutant cells relied on increased EGFR activity to survive.
Based on this discovery, researchers tested two EGFR-inhibiting drugs—cetuximab and afatinib—on both NF1-mutant melanoma cells and other melanoma cells without NF1 mutations. The results were promising: both drugs effectively targeted the NF1-mutant melanoma cells and tumors in mice, showing no impact on melanomas without the NF1 mutation.
Dr. Iman Osman, senior investigator of the study, noted that the findings reveal a vulnerability in NF1-mutant melanoma cells that could be targeted with EGFR inhibitors. These drugs could potentially be used alone or in combination with other immunotherapies to treat melanoma patients whose tumors harbor the NF1 mutation.
The researchers stress that more clinical testing is required to confirm these findings. They plan to develop a clinical trial to test the effectiveness of EGFR inhibitors in patients with NF1-mutant melanoma. If successful, this research could offer new hope for patients battling metastatic melanoma, a disease that claims nearly 10,000 lives annually in the United States.
The study was funded by the National Institutes of Health and the Melanoma Research Foundation. Alongside Ibrahim, Osman, and Schober, several other researchers from NYU Langone Health contributed to the study, including Irineu Illa-Bochaca, George Jour, Eleazar Vega-Saenz de Miera, Joseph Fracasso, Kelly Ruggles, and Jeffrey Weber.
NYU Langone Health is renowned for its high-quality patient care and has consistently ranked among the top academic medical centers in the country.
Related Topics:
