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Master of Public Health

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

AUTHORS

Lehmann BD , Shaver TM , Johnson DB , Li Z , Gonzalez-Ericsson PI , Sanchez V , Shyr Y , Sanders ME , Pietenpol JA , . Molecular cancer research : MCR. 2019 6 11; ().

ABSTRACT

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). Using an independent tumor set we validated a similar rearrangement frequency by fluorescence in situ hybridization. MAP3K8-rearranged melanomas exhibit a low mutational burden and absence of typical UV-mutational patterns. We identified two melanoma cell lines that harbor endogenous truncating MAP3K8 rearrangements that demonstrate exquisite dependency. Rearrangement and amplification of the MAP3K8 locus in melanoma cells results in increased levels of a truncated, active MAP3K8 protein; oncogenic dependency on the aberrant MAP3K8; and, a concomitant resistance to BRAF inhibition and sensitivity to MEK or ERK1/2 inhibition. Our findings reveal and biochemically characterize targetable oncogenic MAP3K8 truncating rearrangements in driver mutation-negative melanoma; and provide insight to therapeutic approaches for patients with these tumors. These data provide rationale for using MEK or ERK inhibitors in a subset of driver-negative, MAPK/ERK-dependent melanomas harboring truncating MAP3K8 rearrangements. Implications: This is the first mechanistic study and therapeutic implications of truncating MAP3K8 rearrangements in driver-negative melanoma.

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