Oncogenic BRAF fusions in mucosal melanomas activate the MAPK pathway and are sensitive to MEK/PI3K inhibition or MEK/CDK4/6 inhibition

Abstract

Despite remarkable progress in cutaneous melanoma genomic profiling, the mutational landscape of primary mucosal melanomas (PMM) remains unclear. Forty-six PMMs underwent targeted exome sequencing of 111 cancer-associated genes. Seventy-six somatic nonsynonymous mutations in 42 genes were observed, and recurrent mutations were noted on eight genes, including TP53 (13%), NRAS (13%), SNX31 (9%), NF1 (9%), KIT (7%) and APC (7%). Mitogen-activated protein kinase (MAPK; 37%), cell cycle (20%) and phosphatidylinositol 3-kinase (PI3K)-mTOR (15%) pathways were frequently mutated. We biologically characterized a novel ZNF767-BRAF fusion found in a vemurafenib-refractory respiratory tract PMM, from which cell line harboring ZNF767-BRAF fusion were established for further molecular analyses. In an independent data set, NFIC-BRAF fusion was identified in an oral PMM case and TMEM178B-BRAF fusion and DGKI-BRAF fusion were identified in two malignant melanomas with a low mutational burden (number of mutation per megabase, 0.8 and 4, respectively). Subsequent analyses revealed that the ZNF767-BRAF fusion protein promotes RAF dimerization and activation of the MAPK pathway. We next tested the in vitro and in vivo efficacy of vemurafenib, trametinib, BKM120 or LEE011 alone and in combination. Trametinib effectively inhibited tumor cell growth in vitro, but the combination of trametinib and BKM120 or LEE011 yielded more than additive anti-tumor effects both in vitro and in vivo in a melanoma cells harboring the BRAF fusion. In conclusion, BRAF fusions define a new molecular subset of PMM that can be targeted therapeutically by the combination of a MEK inhibitor with PI3K or cyclin-dependent kinase 4/6 inhibitors.

BRAF Fusion as a Novel Mechanism of Acquired Resistance to Vemurafenib in BRAFV600E Mutant Melanoma

“…BRAF fusions have been reported as primary driver mutations in a subset of melanomas without a BRAF V600E mutation (26) and have been shown to be associated with resistance to BRAF inhibitors (19,26). Here, we report an AGAP3-BRAF fusion that was detected in a melanoma with a known BRAF V600E mutation at the time of development of resistance to vemurafenib.…”

Fusion Kinases Identified by Genomic Analyses of Sporadic Microsatellite Instability–High Colorectal Cancers

“…Notably, linsitinib, which is usually used for the main purpose of antagonizing IGF1R signaling (34), inhibited the growth of 3T3 cells expressing SLC12A2-INSR. Although it may be difficult to target oncogenic BRAF fusion proteins with specific BRAF inhibitors that are currently available, it is anticipated that tumors with BRAF fusion proteins could be targeted with a combination of MAPK kinase and PI3K inhibitors (35)(36)(37).…”

The convergent roles of the nuclear factor I transcription factors in development and cancer

“…NFI transcription factors have also been implicated in other tumour types such as melanoma, osteosarcoma, neurofibroma, and benign tumours, although their role in these tumours is less clear. In human melanomas, genomic aberrations within the NFI genes, including single nucleotide polymorphism and translocations, have been observed [127][128][129] (Table 1, Table 3). Insertions within Nfia were also observed in tumours derived from an insertional mutagenesis melanoma mouse model [130] (Table 2a), suggesting that NFIA could act as a tumour suppressor in melanoma.…”