Gene Fusions Make Some Pan-Negative Melanomas Sensitive to MEK Inhibitors

Cancer researchers have identified a class of fusion genes that drive melanoma metastasis in the 35% of these skin cancers that lack the previously known driver mutations.

According to senior author Dr. Jeffrey A. Sosman, professor of medicine at Vanderbilt University (Nashville, TN, USA) "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."

Dr. Sosman and his colleagues used a targeted next-generation sequencing (NGS) assay (FoundationOne) and targeted RNA sequencing to search for potential drug targets in a series of pan-negative melanoma specimens.

FoundationOne, the first clinical product from the biotech company Foundation Medicine (Cambridge, MA, USA), is the first commercially available targeted sequencing assay utilizing clinical grade next-generation sequencing (NGS) in routine cancer specimens. This test identifies all classes of genomic alterations (including copy number alterations, insertions, deletions, and rearrangements) in hundreds of cancer-related genes. It complements traditional cancer treatment-decision tools and often expands treatment options by matching each patient with targeted therapies that are relevant to the molecular changes in their tumor.

The investigators reported in the December 15, 2013, issue of the journal Clinical Cancer Research that they had found fusions between the bifunctional 3'-phosphoadenosine 5'-phosphosulfate synthetase 1 gene (PAPSS1) and the V-raf murine sarcoma viral oncogene homolog B1 gene (BRAF) and between the BRAF gene and the tripartite motif-containing 24 gene (TRIM24).

Both classes of BRAF fusions activated the MAPK signaling pathway. The investigators treated fusion gene-bearing cells either with the BRAF inhibitor vemurafenib or with trametinib, an inhibitor of MEK, a protein in the MAPK signaling pathway. Results showed that signaling induced by the BRAF fusions was not responsive to vemurafenib but could be inhibited by trametinib, which implied that the fusions could make melanoma cells harboring them sensitive to MEK inhibitors.

"Performing a sophisticated analysis called targeted next-generation sequencing, it appears that about 8% of pan-negative melanomas have BRAF fusions," said Dr. 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."

This study was funded in part by "Stand up to Cancer" (Pasadena, CA, USA), an organization that raises funds to accelerate the pace of cancer research in order to get new therapies to patients quickly and save lives now.

Related Links:
Vanderbilt University
Foundation Medicine
Stand up to Cancer