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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13402-022-00757-7.