Two BRAF Fusions Discovered in Some Pan-Negative Melanomas

Jeffrey A. Sosman, MD

A Tennessee cancer research center’s discovery of two unique molecular targets known to speed skin-cancer growth has researchers excited that they might soon understand and develop genetic therapies geared toward some of medicine’s most untreatable melanomas.

According to researchers at the Vanderbilt-Ingram Cancer Center in Nashville, about 35 percent of all skin cancers are pan-negative, meaning they lack discernible driver mutations in the genesBRAF,NRAS,KIT,GNAQ, andGNA11.

Discovering erroneous fusions of two or more genes that generate abnormal proteins and lead to cancer-cell growth is critical to developing successful therapies, according to Jeffrey A. Sosman, MD, professor of medicine at Vanderbilt-Ingram Cancer Center in Nashville, Tennessee.

“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 either being developed or are already FDA approved,” Sosman said.

William Pao, MD, PhD, a physician-scientist at Vanderbilt-Ingram Cancer Center, coauthored this study with Sosman. The research team found, in one cancer patient’s melanoma sample, a fusion between two genes,PAPSS1andBRAF, which they called PAPSS1-BRAF. They identified a second novel BRAF fusion, called TRIM24-BRAF, after evaluating melanomas from another 51 patients, 24 of whom were pan-negative, according to Sosman.

Further studies revealed that both BRAF fusions activated the MAPK signaling pathway. They treated these BRAF fusion-bearing cells with the BRAF inhibitor vemurafenib or with trametinib, a drug that inhibits MEK, a protein in the MAPK signaling.

They found that signaling induced by the BRAF fusions was not responsive to vemurafenib, but could be inhibited by trametinib. This led the researchers to suggest that the novel fusions they identified could produce melanoma cells sensitive to MEK inhibitors, according to Sosman.