Selumetinib is active in Ras pathway–mutated ALL cells in vitro and is associated with reduced levels of p-ERK and induction of Bim and cleaved Parp. Histogram showing densitometry values of p-ERK levels relative to ERK as assessed by western analyses for both WT (black bars) and Ras pathway–mutated samples (gray bars) (A). Bar chart of GI50 values as assessed by 3-(4,5 dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl-2-(4-sulfophenyl)-2H-tetrazolium assay after dosing with selumetinib for both Ras pathway–positive/p-ERK–positive samples (red bars, n = 5) and those negative for Ras pathway mutation and p-ERK (blue bars, n = 5) (B). Western analyses of ALL cell lysates from patients L897 (KRAS), L924 (KRAS), and L949 (WT) after treatment with a range of concentrations of selumetinib. Blots were probed for p-ERK, ERK2, Bim, cleaved Parp, and α-tubulin. In the case of L949, a positive control for p-ERK expression (CCRF-CEM cells) was included (C). Similar analyses of spleen cells from NOD SCID γ null mice engrafted with patient ALL cells as a source of primary-derived material (D). Primagrafts from duplicate mice implanted with blasts from patients L897 (KRAS) and L779 (NRAS) were treated with varying concentrations of selumetinib for 24 hours and processed for western analysis.