Melanoma has the highest mortality rate of all
skin cancers and a major cause of treatment failure is drug resistance.
Tumors heterogeneity requires novel therapeutic strategies and new drugs targeting multiple pathways. One of the new approaches is targeting the scaffolding function of
tumor related
proteins such as
focal adhesion kinase (FAK). FAK is overexpressed in most solid
tumors and is involved in multiple
protein-
protein interactions critical for
tumor cell survival,
tumor neovascularization, progression and
metastasis. In this study, we investigated the anticancer activity of the FAK scaffold inhibitor C4, targeted to the FAK-VEGFR-3 complex, against
melanomas. We compared C4 inhibitory effects in BRAF mutant vs BRAF wild type
melanomas. C4 effectively caused
melanoma tumor regression in vivo, when administered alone and sensitized
tumors to
chemotherapy. The most dramatic effect of C4 was related to reduction of vasculature of both BRAF wild type and V600E mutant xenograft
tumors. The in vivo effects of C4 were assessed in xenograft models using non-invasive multimodality imaging in conjunction with histologic and molecular biology methods. C4 inhibited cell viability, adhesion and motility of
melanoma and endothelial cells, specifically blocked phosphorylation of
VEGFR-3 and FAK and disrupted their complexes. Specificity of in vivo effects for C4 were confirmed by a decrease in
tumor FAK and
VEGFR-3 phosphorylation, reduction of vasculogenesis and reduced blood flow. Our collective observations provide evidence that a small molecule inhibitor targeted to the FAK
protein-
protein interaction site successfully inhibits
melanoma growth through dual targeting of
tumor and endothelial cells and is effective against both BRAF wild type and mutant
melanomas.