New molecular targets offer potential treatment option for hard-to-treat melanoma

Two novel BRAF fusions have been identified in melanomas that were previously considered to be negative for molecular targets. Melanomas with these fusions are potentially sensitive to the group of cancer drugs known as mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitors.

"About 35% of melanomas are, as of today, 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 A. Sosman, MD, of Vanderbilt-Ingram Cancer Center in Nashville, Tennessee. Researchers 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. In some cancers, two or more genes fuse erroneously to produce abnormal proteins, which can function as the "drivers" of those cancers.

"Performing a sophisticated analysis called targeted next-generation sequencing, it appears that about 8% of pan-negative melanomas have BRAF fusions," said Sosman. "Our results are important because they obviously suggest that there probably are other, as yet unidentified, molecular changes that make these melanomas susceptible to drugs that are available right now."

In a pan-negative melanoma sample from one of their patients, the research team identified a fusion between two genes, PAPSS1 and BRAF, which they called PAPSS1-BRAF. They then evaluated melanomas from an additional 51 patients, 24 of which were pan-negative. In one of these 24 pan-negative samples, they identified a second novel BRAF fusion, called TRIM24-BRAF.

The investigators conducted further studies in the laboratory and found that both BRAF fusions activated a pathway in the cancer cells called the mitogen-activated protein kinase (MAPK)-signaling pathway. They then treated these fusion-bearing cells either with the BRAF inhibitor vemurafenib or with trametinib, a drug that inhibits a protein in the MAPK-signaling pathway called MEK. They found that signaling induced by the BRAF fusions was not responsive to vemurafenib but could be inhibited by trametinib, which led them to suggest that the novel fusions they identified could make the melanoma cells harboring them sensitive to MEK inhibitors.

This research was supported by Stand Up to Cancer (SU2C), a charitable initiative supporting ground-breaking research aimed at getting new cancer treatments to patients in an accelerated timeframe. The research was published in Clinical Cancer Research (2013; doi:10.1158/1078-0432.CCR-13-1746).

"One of the primary objectives of Stand Up To Cancer is to accelerate the development of effective treatments to help patients. This research from Drs. Sosman and Pao advances that objective because identifying novel genetic mutations helps identify targets that might be sensitive to existing or future drug therapies," said William G. Nelson, MD, PhD, a member of the SU2C Scientific Advisory Committee and director of the Sidney Kimmel Comprehensive Cancer Center, at Johns Hopkins University in Baltimore, MD.

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