Identification of targetable recurrent MAP3K8 rearrangements in melanomas lacking known driver mutations

Melanomas are characterized by driver and loss-of-function mutations that promote mitogen-activated protein kinase (MAPK) signaling. MEK inhibitors are approved for use in BRAF-mutated melanoma; however, early-phase clinical trials show occasional responses in driver-negative melanoma, suggesting other alterations conferring MAPK/ERK dependency. To identify additional structural alterations in melanoma we evaluated RNA-Seq from a set of known MAPK/ERK regulators using a novel population-based algorithm in The Cancer Genome Atlas (TCGA). We identified recurrent MAP3K8 rearrangements in 1.7% of melanomas in TCGA, occurring in over 15% of tumors without known driver mutations (BRAF, NRAS, KIT, GNAQ, GNA11 and NF1). We identified two melanoma cell lines that harbor endogenous truncating MAP3K8 rearrangements that demonstrate exquisite dependency.