ERBB4 Drives the Proliferation of BRAF-WT Melanoma Cell Lines

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 effective 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 elevated ERBB4 transcription strongly correlates with RAS gene or NF1 mutations that stimulate RAS signaling. Thus, these results have led us to hypothesize that elevated ERBB4 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. Ectopic expression of wild-type ERBB4 stimulates clonogenic proliferation of the IPC-298, MEL-JUSO, MeWo, and SK-MEL-2 BRAF WT melanoma cell lines, whereas ectopic expression of a dominant-negative (K751M) ERBB4 mutant allele inhibits clonogenic proliferation of these same cell lines. Ectopic expression of a dominant-negative ERBB4 mutant allele inhibits anchorage-independent proliferation of MEL-JUSO cells and ectopic expression of a dominant-negative ERBB2 mutant alleles inhibits clonogenic proliferation of MEL-JUSO cells. These data suggest that elevated signaling by ERBB4-ERBB2 heterodimers cooperates with elevated RAS signaling to drive the proliferation of some BRAF WT tumors and that combination therapies that target these two signaling pathways may be effective against these BRAF WT tumors.