ERBB4 Drives the Proliferation of BRAF-WT Melanoma Cell Lines

Abstract

AbstractMetastatic 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.