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) have a worse prognosis than those with wildtype (BRAF) tumors. Unexpectedly, interim AVAST-M Phase III trial data reported benefit from adjuvant anti-VEGF bevacizumab only in the BRAF 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 knock-in on a BRAF background.

Results: Compared with BRAF cells, isogenic BRAF 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 xenografts, inducing significant tumor growth delay, reduced vascularity and increased necrosis. We identified 814 differentially expressed genes in isogenic BRAF/BRAF clones. Of 61 genes concordantly deregulated in clinical melanomas ROR2 was one of the most upregulated by BRAF. ROR2 was shown to be RAF-MEK regulated in BRAF cells and its depletion suppressed VEGF secretion down to BRAF levels. The ROR2 ligand WNT5A was also overexpressed in BRAF melanomas, and in ROR2-overexpressing BRAF 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 melanomas, suggesting that this axis has potential therapeutic relevance.