The effect of E7080, a VEGFR and FGFR tyrosine kinase inhibitor (TKI), on BRAF wild-type melanoma.

8566 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. This study examines the mode of action of E7080 in preclinical melanoma models Methods: Mutational status of 18 genes (9 RTKs, 7 oncogenes and 2 tumor suppressor genes) was determined in 14 human melanoma cell lines. Gene profile and biomarkers of anti-angiogenesis and anti-tumor activity of E7080 were investigated in vitro and in vivo by gene expression analysis in a melanoma cell line panel and in human melanoma tissues. Results: 18 types of mutation (mu) were found among 9 RTKs in ten of 14 melanoma cell lines. 2 mu of BRAF, 9 mu of TP53, 3 mu of PTEN, 2 mu of CDKN2a and 1 mu of NRAS were also found among 9, 9, 3, 2 and 1 melanoma of 14 cell lines, respectively. 4 of the 5 melanoma with BRAF wild type (wt) were the most sensitive to E7080 in mouse xenograft models, while 5 of the 6 with BRAFmu/PTENwt were the most resistant, suggesting 3 sub-groups for s...