Metastatic skin cutaneous melanomas remain a significant clinical problem. In particular, those melanomas that do not contain a gain-of-function BRAF allele remain challenging to treat because of the paucity of targets for therapeutic intervention. Thus, here we investigate the role of the ERBB4 receptor tyrosine kinase in skin cutaneous melanomas that contain wild-type BRAF alleles ("BRAF WT melanomas"). We have performed in silico analyses of a public repository (The Cancer Genome Atlas - TCGA) of skin cutaneous melanoma gene expression and mutation data (TCGA-SKCM data set). These analyses demonstrate that ERBB4 overexpression strongly correlates with RAS gene or NF1 mutations that stimulate RAS signaling. Thus, these results have led us to hypothesize that elevated ERBB4 signaling promotes PI3K signaling, which cooperates with elevated RAS signaling to drive BRAF WT melanomas. We have tested this hypothesis using commercially available BRAF WT melanoma cell lines. Overexpression of wild-type ERBB4 stimulates clonogenic proliferation of the MEL-JUSO, MEWO, and IPC-298 BRAF WT melanoma cell lines. Moreover, overexpression of a dominant-negative ERBB4 (K751M) mutant inhibits clonogenic proliferation of the MEL-JUSO and MEWO cell lines. We discuss how these results may impact strategies for treating metastatic BRAF WT skin cutaneous melanomas.

David J. Riese II has been a consultant for Eli Lilly & Co., ImClone Systems, and Bristol-Myers Squibb.

This research has been funded by an Auburn University Internal Grants Program award to DJR, an Auburn University Research Initiative in Cancer (AURIC) fellowship to RLC, the US Department of Education GAANN Graduate Fellowship Program in Biological & Pharmaceutical Engineering Award No. P200A120244 to Auburn University, an Auburn University Presidential Graduate Research Fellowship to LML, and other support from AURIC, the Department of Drug Discovery and Development, and the Harrison College of Pharmacy.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The Cancer Genome Atlas (TCGA) Skin Cutaneous Melanoma (SKCM) dataset: https://portal.gdc.cancer.gov/projects/TCGA-SKCM

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