Increased activity in a specific biological pathway may explain why many patients with a deadly form of skin cancer do not respond to the latest cancer treatments, a new study shows.
Publishing in the journal Cancer Research online June 10, the study featured data generated from experiments with human tissues and cells from patients with advanced melanoma that were implanted into mice. Results uncovered therapeutic targets that could limit melanoma growth in patients whose cancer failed to respond to initial treatment with immune checkpoint inhibitors.
Led by researchers at NYU Langone Health and its Perlmutter Cancer Center, the study focused on a subgroup of melanoma patients with mutations in the neurofibromin 1 (NF1) gene. NF1 mutations — random changes in the molecular „letters“ that make up this gene’s DNA code — are just one type among several mutations, including those in the BRAF, NRAS, and PARP genes, that are linked to many cases of cancer, particularly melanoma. As many as 27% of melanoma patients are estimated to have NF1 mutations.
While immunotherapy, which stimulates the immune system to attack cancer cells as it would an invading virus, has proved to be a successful treatment, it does not work well for more than half of NF1-mutant melanoma patients.
To investigate why these patients were treatment resistant, investigators examined tumor cells from 30 melanoma patients who did not respond to immunotherapy. NF1 mutations were found in 40% of these melanoma samples. The samples came from NYU Langone’s extensive repository from more than 6,000 melanoma patients.
Molecular testing showed that the signaling pathway built around a protein called epidermal growth factor receptor (EGFR) was more active in NF1 mutant melanoma cells than in cells with other melanoma-gene mutations. Increased EGFR activity has long been linked to abnormal cell growth in tumors and shorter survival with various cancers. The researchers also found that NF1 mutant melanoma cells depended on increased EGFR activity for survival, regardless of the presence of other mutations.
Because EGFR-inhibiting drugs are already used to treat some head and neck cancers, as well as colorectal and lung cancers, researchers then tested two drugs in the class, cetuximab and afatinib, in both NF1 mutant cell cultures and cancer cell lines without NF1 mutations. After transplanting both tumor cell types into mice and treating them with these drugs, results showed that both EGFR inhibitors were effective against cells and transplanted tumors with NF1 mutations, and they had no effect on melanomas without NF1 mutations.
Metastatic melanoma, as the disease is formally called, kills nearly 10,000 Americans annually.
Funding for the study was provided by National Institutes of Health grants P50CA225450, U54CA263001, and P30CA016087. Additional funding support was provided by Melanoma Research Foundation grant 1287389.
