A team of researchers at NYU Langone Health and the Perlmutter Cancer Center has identified a potential therapeutic strategy for melanoma patients whose tumors harbor mutations in the neurofibromin 1 (NF1) gene and who do not respond to current immunotherapy treatments. The study, published in Cancer Research, showed that EGFR inhibitor drugs, already approved for the treatment of head and neck, lung, and colorectal cancers, could be an effective treatment option for this melanoma subtype.
“There is a pressing need for new drug therapies for melanoma patients with neurofibromin 1 mutations that do not respond to the latest immunotherapy, and for which there are no subsequent effective treatment options,” said study lead author Milad Ibrahim, PhD, a postdoctoral fellow in the lab of Iman Osman, MD, at NYU Grossman School of Medicine.
To begin the inquiry into why some melanomas with NF1 mutations resist immune checkpoint inhibitors (ICIs), the team examined tumor samples from 30 patients who had not responded to immunotherapy. NF1 mutations were found in 40% of these cases. Using patient-derived short-term cultures and multiomic analyses, the researchers discovered that the epidermal growth factor receptor (EGFR) pathway was significantly more active in NF1-mutant cells than in other melanoma subtypes.
“Differential gene expression analysis revealed that the epidermal growth factor receptor (EGFR) is highly expressed and active in NF1 mutant melanoma cells, where it hyper-activates ERK and AKT, leading to increased tumor cell proliferation, survival, and growth,” the researchers wrote.
Building on this finding, the team then tested whether EGFR inhibitor drugs could suppress NF1-mutant melanoma. Two such drugs, cetuximab (a monoclonal antibody) and afatinib (a small-molecule inhibitor), were tested on melanoma cell lines and in mouse models implanted with human tumor cells.
Both drugs were found to inhibit tumor growth in NF1-mutant melanoma models but had no effect on tumors without NF1 mutations. “Our study results reveal a unique vulnerability in melanoma patients with neurofibromin 1 mutations, that an overexpression of the epidermal growth factor receptor pathway is essential for their survival and growth,” said senior author Osman, director of NYU Langone’s interdisciplinary melanoma program.
The research builds on prior knowledge that NF1 acts as a tumor suppressor by negatively regulating RAS signaling pathways, including the MAPK and PI3K-AKT pathways, which are implicated in cell proliferation and survival. Previous therapies targeting these downstream pathways, like MEK inhibitors, have been less effective in NF1-mutant melanomas.
“Our studies revealed that NF1Mut melanoma cells are more sensitive to EGFR inhibition than other melanoma subtypes and that patients with NF1Mut melanoma might benefit from treatment with the monoclonal EGFR inhibitory antibody cetuximab or the second-generation small molecule EGFR inhibitor afatinib, irrespective of their NRAS and BRAF mutation status,” the researchers wrote.
While first-generation EGFR inhibitors like gefitinib and erlotinib failed in earlier melanoma trials, the NYU team noted that patient selection in future trials based on NF1 mutation status could yield more positive results.
“While further tests are needed, our results support a novel approach of deploying EGFR inhibitors either alone or in combination with other immunotherapies for treatment of melanoma patients whose tumors harbor NF1 mutation,” said co-senior author Markus Schober, PhD, an associate professor of dermatology at NYU Grossman School of Medicine.
The findings could provide a more precise approach to melanoma treatment by identifying a molecular vulnerability specific to NF1-mutant tumors, which would benefit a significant portion of patients currently without viable treatment options.
The NYU team now plans to advance EGFR inhibitors into clinical trials to assess their safety and efficacy in NF1-mutant melanoma patients. The researchers are also examining possible combination therapies that would enhance the anti-tumor effects of EGFR inhibition. Early results suggest drugs targeting lipid peroxidation and ferroptosis or additional receptor tyrosine kinases could be part of an effective combination drug strategy.
