Cancer researchers, led by investigators at Vanderbilt-Ingram Cancer Center, have identified two novel gene fusions in melanoma that may be responsive to existing cancer therapies. Melanoma is the most deadly form of skin cancer.
The study was published in Clinical Cancer Research, a journal of the American Association for Cancer Research.
“About 35 percent of melanomas are considered ‘pan-negative,’ which means they are devoid of any previously known driver mutations in the genes BRAF, NRAS, KIT, GNAQ and GNA11,” said Jeffrey Sosman, M.D., professor of Medicine and leader of the Vanderbilt Melanoma Program. “We have been interested in looking at patients whose tumors have none of these driver mutations to see what their tumors do have that can be targeted therapeutically.”
Sosman, co-principal investigator William Pao, M.D., Ph.D., director of the Division of Hematology and Oncology and director of Personalized Cancer Medicine at VICC, and their colleagues evaluated a pan-negative melanoma sample from one of their patients.
The group used the FoundationOne testing platform to perform a sophisticated analysis known as targeted next-generation sequencing and identified an unusual fusion between two genes, BRAF and PAPSS1. They evaluated melanomas from an additional 51 patients, 24 of which were pan-negative, and in one of those pan-negative samples they found a second novel BRAF fusion called TRIM24-BRAF.
Based on this research and additional studies mining publicly available data from the Cancer Genome Atlas, up to 8 percent of pan-negative melanomas may have BRAF fusions.
The investigators engineered fusion-bearing cells and found that both newly identified BRAF fusions activated a specific signaling pathway called the MAPK pathway. The investigators then treated the fusion-bearing cells with two types of drugs — the BRAF inhibitor vemurafenib, and trametinib, a drug that inhibits a MAPK signaling pathway protein called MEK. While the fusion-induced signaling was not responsive to the BRAF inhibitor, it was inhibited by trametinib, which suggests that melanoma cells harboring the novel fusions could be sensitive to MEK inhibitor therapy.
“There is immense value in identifying novel mutations in untreatable cancers because many of them are clinically relevant, which means they may be sensitive to drugs that are already FDA approved or are in development,” said Sosman.
“BRAF fusions have previously been identified in other cancer types, but this is the first time they have been characterized in melanoma,” said first author and Department of Cancer Biology doctoral candidate Katherine Hutchinson. “This discovery means we are getting closer to filling in the gap of unknowns and making personalized medicine a reality for even more patients.”
Other investigators who participated in the study include Brian Lehmann, Ph.D., Pamela Lyle, M.D., Cindy Vnencak-Jones, Ph.D., Jennifer Pietenpol, Ph.D., Igor Puzanov, M.D., MSCI, Vanderbilt, Doron Lipson, Ph.D., Philip Stephens, Ph.D., Geoff Otto, Ph.D., Vincent Miller, M.D., Foundation Medicine, Cambridge, Mass., and Jeffrey Ross, M.D., Foundation Medicine and Albany Medical College.
The study was funded by Stand Up to Cancer (SU2C) Melanoma Dream Team and Innovative Research grants, James C. Bradford Family Foundation, American Cancer Society, Joanna M. Nicolay Melanoma Foundation 2013 Research Scholar Award, and the National Cancer Institute, which is a division of the National Institutes of Health (5K24 CA097588-09, CA95131).
