Is ERBB4 a Driver of BRAF WT Melanomas?

Combining immune checkpoint inhibitors with BRAF and MEK inhibitors has enabled significant improvements in treating metastatic skin cutaneous melanomas that possess activating mutations in the BRAF gene (“BRAF mutant melanomas”). In contrast, actionable and specific targets in metastatic cutaneous melanomas that contain the wild-type BRAF gene

(“BRAF WT melanomas”) have yet to be discovered, hindering the development of more effective strategies for treating these tumors. Here we propose to address that knowledge gap by validating a candidate target in BRAF WT melanomas and strategies for therapeutic intervention. Published and preliminary data have led to the following hypothesis: ERBB4

mutations or elevated ERBB4 transcription increase signaling by ERBB4-EGFR or ERBB4- ERBB2 heterodimers, resulting in increased PI3 kinase signaling, cooperation with NF1 or RAS gene mutations, and increased proliferation of BRAF WT melanomas. We will test aspects of this hypothesis with two specific aims: (1) Which ERBB4 mutants found in BRAF

WT melanomas cause increased proliferation of BRAF WT melanoma cell lines? (2) Is EGFR, ERBB2, or the PI3K pathway required for proliferation of the ERBB4-dependent, BRAF-WT melanoma cell lines? We estimate that the predicted outcome of these studies will lead to effective strategies for treating approximately 30% of metastatic BRAF WT

melanomas, revolutionizing the care of patients that carry these aggressive skin cancers.