Abstract B93: Sensitivity to the MEK inhibitor, E6201, is associated with mutant BRAF status and is inversely correlated with pAKT expression levels in melanoma cell lines

Abstract

Abstract Inhibition of the RAS/RAF/MEK/ERK signaling pathway has emerged as a promising therapeutic strategy for melanoma given the high frequency of BRAF and NRAS mutations in this tumor type. Sensitivity to E6201, an inhibitor of MEK1 and other cancer relevant kinases, was assessed in a panel of 32 cell lines for which the mutation status of common melanoma genes was known. The majority (24/32) of the melanoma cell lines were sensitive to E6201, resulting in G1-cell cycle arrest and cell death in 11 sensitive cell lines and cell cycle arrest but not cell death in two sensitive lines. Xenograft studies revealed that E6201 exhibited a cytotoxic effect in vivo, even in cell lines where only a cytostatic effect was observed in vitro. Among cell lines carrying mutations in BRAF, or NRAS, sensitivity to E6201 was associated with wildtype PTEN status (p<0.03). When the cell lines were classified based on basal pERK levels rather than BRAF mutation status, high levels of pAKT correlated with insensitivity to E6201 (p<0.04). Indeed, high levels of pAKT correlated with E6201 insensitivity independent of BRAF or PTEN mutation status (p<0.03). Together these data demonstrate the cytostatic and cytotoxic activity of E6201 in BRAF mutant melanoma cell lines in vitro and in vivo and, furthermore, indicate that quantification of pAKT levels may have clinical utility as a biomarker of E6201 resistance. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B93.