ERBB4 Mutant Alleles May Drive BRAF WT Melanomas

Abstract

AbstractMetastatic skin cutaneous melanomas that contain wild-type BRAF alleles (“BRAF WT melanomas”) remain a significant clinical challenge, primarily because of the paucity of targets for therapeutic intervention. In prior work, in silico analyses of The Cancer Genome Atlas Skin Cutaneous Melanoma (TCGA-SKCM) dataset suggested that elevated transcription of the gene that encodes the ERBB4 receptor tyrosine kinase may drive BRAF WT melanomas. Moreover, that prior work demonstrated that expression of the wild-type ERBB4 gene (WT ERBB4) stimulates clonogenic proliferation by the MEL-JUSO, MeWo, and IPC-298 human BRAF WT melanoma cell lines. Moreover, expression of a dominant-negative (K751M) ERBB4 mutant (ERBB4 DN) inhibits clonogenic proliferation by the MEL-JUSO and MeWo cell lines.Here we have extended these findings by investigating the role of ERBB4 mutant alleles in BRAF WT melanomas. In silico analyses of the TCGA-SKCM BRAF WT melanoma dataset indicates that ERBB4 missense mutant alleles occur in a non-random manner, suggesting that melanomagenesis selects for the ERBB4 missense mutant alleles. Specifically, ERBB4 missense mutant alleles affect amino acid residues that are weakly correlated with residues conserved in the ERBB3 extracellular domains and the EGFR tyrosine kinase domain. The occurrence of ERBB4 missense mutant alleles in the TCGA-SKCM BRAF WT melanoma dataset is weakly inversely correlated with events that cause ERBB4-independent PI3K pathway signaling and is strongly correlated with events that cause elevated RAS pathway signaling. Thus, the in silico analyses suggest that ERBB4 mutant alleles stimulate PI3K signaling, which cooperates with elevated RAS signaling to drive BRAF WT melanomas. Moreover, the in silico analyses have prioritized the ERBB4 mutant alleles as candidate drivers of BRAF WT melanomas. One of the prioritized ERBB4 mutant alleles (P759L) stimulates greater clonogenic proliferation of MEL-JUSO cells than does WT ERBB4. Thus, our in silico prioritization strategy may effectively identify ERBB4 mutants that drive BRAF WT melanomas. Finally, the results of our in silico analyses suggest that ERBB4-dependent, BRAF WT melanomas may be effectively treated by a combination of a PI3K pathway inhibitor and a RAS pathway inhibitor.