Potentially Actionable MAP3K8 Alterations Are Common in Spitzoid Melanoma

Spitzoid melanoma is a melanoma variant that primarily affects children and adolescents. Fusions of ALK, RET, NTRK1, NTRK3, MET, ROS1, and BRAF are known drivers of these tumors, but approximately half of spitzoid melanomas have no known genetic driver. Newman and colleagues report the case of a patient with recurrent, metastatic spitzoid melanoma who was enrolled on an institutional clinical genomics study. Comprehensive whole-genome, whole-exome, and whole-transcriptome analysis failed to identify any of the known oncogenic drivers of spitzoid melanoma but revealed an in-frame fusion affecting MAP3K8 (also known as COT), which encodes a serine–threonine kinase that phosphorylates and activates MEK and has been implicated in BRAF inhibitor resistance. Immunohistochemistry confirmed that MEK1/2 was phosphorylated, and the patient was treated with the MEK inhibitor trametinib. Although the lesions initially were reduced in size and number based on examination and PET, treatment was discontinued due to cardiotoxicity and lack of sustained response. RNA sequencing (RNA-seq) of tumors from an additional 49 patients with spitzoid melanoma revealed that 16/49 (33%) tumors harbored either an in-frame fusion or C-terminal truncation of MAP3K8, making MAP3K8 alterations the most common genetic event in this disease. All alterations led to loss of the final exon of MAP3K8, which encodes the autoinhibitory C-terminal domain, and were associated with MEK1/2 phosphorylation in paraffin-embedded tissue sections. Of note, locus-specific analysis of RNA-seq data from 472 adult melanoma samples in The Cancer Genome Atlas identified 7 samples (1.5%) with MAP3K8 fusion or truncation, none of which had any other MAPK pathway mutation, suggesting that MAP3K8 alterations may also be drivers in some adult melanomas. In addition to providing an example of how comprehensive sequencing of individual patients can lead to broader insights into tumor etiology, these findings suggest that MAP3K8 alterations are more common than previously appreciated and may potentially be predictive of response to MEK inhibitors.

Newman S, Fan L, Pribnow A, Silkov A, Rice SV, Lee S, et al. Clinical genome sequencing uncovers potentially targetable truncations and fusions of MAP3K8 in spitzoid and other melanomas. Nat Med 2019;25:597–602.

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