8567 Background: E7080 is a TKI targeting VEGFR1-3, FGFR1-4, KIT, RET and PDGFR. Anti-tumor activity has been observed in melanoma patients in phase I. The objective of this study was to examine the effect of E7080 alone and in combination with PLX-4032 on tumor response, gene expression and tumor microvasculature in BRAFmu melanoma. Methods: BRAF mutant (mu) cell lines were created by transfection of BRAF V600E constructs into BRAF wild type (wt) cell lines. Anti-tumor activity of E7080 alone or in combination with the selective BRAF inhibitor PLX-4032 was examined in xenografted models bearing mock and BRAFmu transfectants. Results: The ratio of ANGPT1/2 expression was significantly higher in BRAFmu/ PTENwt compared to BRAFwt/PTENwt and BRAFmu/PTENmu among 14 melanoma cell lines. ANGPT1 expression was up-regulated in BRAFmu by 330%, and ANGPT2 in PTENmu by 290% compared to wt. PLX-4032 decreased ANGPT1 expression and pericyte coverage of tumor vessels in BRAFmu/PTENwt A375 melanoma. Similarly, overexpression of BRAF V600E in BRAFwt SK-MEL-2 melanoma resulted in increased ANGPT1 expression along with increased pericyte coverage. E7080 at 3, 10, 30 to 100 mg/kg showed significant anti-tumor activity against mock transfectants, but only at 100 mg/kg against BRAF V600E transfectants. Combination of E7080 at 10 mg/kg with PLX-4032 at 100 mg/kg showed synergistic anti-tumor activity against A375 melanoma and caused tumor regression, not observed by either single agent E7080 or PLX-4032. E7080 alone increased pericyte coverage of tumor vessels, but in combination with PLX-4032 resulted in marked decreased in pericyte coverage and microvessel density. Conclusions: The BRAFmu/ PTENwt melanomas studied demonstrate high pericyte coverage and resistance to E7080. Combination of E7080 with PLX-4032 achieves synergistic antitumor effect with enhanced reduction of pericyte coverage. These data provide a mechanistic basis for clinical study of BRAF inhibitors in combination with VEGFR and FGFR targeted agents.