WNT5A-ROR2 axis mediates VEGF dependence of BRAF mutant melanoma

Purpose: Despite recent advances, approximately 50% of patient with metastatic melanoma eventually succumb to the disease. Patients with melanomas harboring a BRAF mutation (BRAF^Mut) have a worse prognosis than those with wildtype (BRAF^WT) tumors. Unexpectedly, interim AVAST-M Phase III trial data reported benefit from adjuvant anti-VEGF bevacizumab only in the BRAF^Mut group. We sought to find mechanisms underpinning this sensitivity. Methods: We investigated this finding in vitro and in vivo using melanoma cell lines and clones generated by BRAF^V600E knock-in on a BRAF^WT background. Results: Compared with BRAF^WT cells, isogenic BRAF^V600E clones secreted more VEGF and exhibited accelerated growth rates as spheroids and xenografts, which were more vascular and proliferative. Recapitulating AVAST-M findings, bevacizumab affected only BRAF^V600E xenografts, inducing significant tumor growth delay, reduced vascularity and increased necrosis. We identified 814 differentially expressed genes in isogenic BRAF^V600E/BRAF^WT clones. Of 61 genes concordantly deregulated in clinical melanomas ROR2 was one of the most upregulated by BRAF^V600E. ROR2 was shown to be RAF-MEK regulated in BRAF^V600E cells and its depletion suppressed VEGF secretion down to BRAF^WT levels. The ROR2 ligand WNT5A was also overexpressed in BRAF^Mut melanomas, and in ROR2-overexpressing BRAF^V600E cells MEK inhibition downregulated WNT5A and VEGF secretion. Conclusions: These data implicate WNT5A-ROR2 in VEGF secretion, vascularity, adverse outcomes and bevacizumab sensitivity of BRAF^Mut melanomas, suggesting that this axis has potential therapeutic relevance.