title: A FAK scaffold inhibitor disrupts FAK and VEGFR-3 signaling and blocks melanoma growth by targeting both tumor and endothelial cells.
abstract: 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.
authors.affiliation: a Department of Surgical Oncology ; Roswell Park Cancer Institute ; Buffalo , NY USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Kurenova
authors.forename: Deniz
authors.initials: D
authors.lastname: Ucar
authors.forename: Jianqun
authors.initials: J
authors.lastname: Liao
authors.forename: Michael
authors.initials: M
authors.lastname: Yemma
authors.forename: Priyanka
authors.initials: P
authors.lastname: Gogate
authors.forename: Wiam
authors.initials: W
authors.lastname: Bshara
authors.forename: Ulas
authors.initials: U
authors.lastname: Sunar
authors.forename: Mukund
authors.initials: M
authors.lastname: Seshadri
authors.forename: Steven N
authors.initials: SN
authors.lastname: Hochwald
authors.forename: William G
authors.initials: WG
authors.lastname: Cance
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005029:Ethylenediamines / Q000494:pharmacology* / Q000627:therapeutic use; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D064593:Heterografts; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D051379:Mice; D055503:Protein Multimerization / Q000187:drug effects; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D005029:Ethylenediamines; C004664:chloropyramine; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; D051416:Focal Adhesion Protein-Tyrosine Kinases; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf
keywords: FAK; FAK-VEGFR-3 interaction; VEGFR3; angiogenesis; melanoma; protein-protein interaction; scaffold Inhibitor