Recurrent BRAF kinase fusions in melanocytic tumors offer an opportunity for targeted therapy

Abstract

Summary BRAF is the most prevalent oncogene and an important therapeutic target in melanoma. In some cancers BRAF is activated by rearrangements that fuse its kinase domain to 5’ partner genes. We examined 848 comparative genomic hybridization profiles of melanocytic tumors and found copy number transitions within BRAF in 10 tumors, of which six could be further characterized by sequencing. In all, the BRAF kinase domain was fused in-frame to six different N-terminal partners. No other mutations were identified in melanoma oncogenes. One of seven melanoma cell lines without known oncogenic mutations harbored a similar BRAF fusion, which constitutively activated the MAP-kinase pathway. Sorafenib, but not vemurafenib, could block MAP-kinase pathway activation and proliferation of the cell line at clinically relevant concentrations, whereas BRAFV600E mutant melanoma cell lines were significantly more sensitive to vemurafenib. The patient from whom the cell line was derived showed a durable clinical response to sorafenib.

High-Throughput Genomic Profiling of Adult Solid Tumors Reveals Novel Insights into Cancer Pathogenesis

“…BRAF fusions have been described in melanoma, thyroid cancers, and pediatric brain cancers (29). A single thyroid papillary carcinoma was found with a MAD1L1-BRAF fusion identified previously in melanoma (30). We also observed the known TMEM106B-ROS1 fusion (31) in a liver cholangiocarcinoma.…”

Targeted agents and immunotherapies: optimizing outcomes in melanoma

“…An additional 3-5% of melanomas harbour other forms of genetic alteration in BRAF that are also considered to be oncogenic 5 . These aberrations are divided between missense mutations in the region adjacent to V600 (within exon 15) or distant from this site (within exon 11), and BRAF translocations (also referred to as fusions) [25][26][27][28] . In melanomas and other cancers, dozens of sites in BRAF exons 11 and 15 have been found to harbour missense mutations, but only a small number have been functionally characterized.…”

“…Those that have been investigated seem to result in activation of the MAPK pathway, in cooperation with CRAF 31 . BRAF translocations generate proteins in which the kinase domain of BRAF is fused with regulatory domains of vari ous other proteins 27 . Preclinical evidence indicates that the currently available BRAF inhibitors do not inhibit these non-V600-mutant forms of BRAF, nor BRAF fusion proteins 27,32 ; however, MEK inhibitors are effective in suppressing signalling downstream of these BRAF mutants in experimental systems, and anecdotal reports of patients with such alterations responding to MEK inhibitors have been published [26][27][28] .…”

“…Responses to MEK inhibitors have also been observed in patients with tumours harbouring non-V600 BRAF mutations, or a BRAF/NRAS-wild-type status [26][27][28] ; however, the numbers of patients included were small, limiting comparisons between the outcomes of these groups and those observed with MEK-inhibitor monotherapy in BRAF-V600-mutant and NRAS-mutant populations. Nevertheless, the current evidence in NRAS-mutant melanoma indicates that investi gation of MEK-inhibitor-based combination regimens seems justified.…”

Clinical activity of the MEK inhibitor trametinib in metastatic melanoma containing BRAF kinase fusion

“…Recently, BRAF fusions have been reported in 4-8% of melanomas without oncogenic point mutations in BRAF , NRAS or KIT (Botton et al, 2013; Hutchinson et al, 2013). BRAF fusions have a full and intact kinase domain comparable to the one of wild-type BRAF , and selective mutant-BRAF inhibitors (e.g.…”