Figure 5: MAP3K8 is a predictive marker for MEK inhibitor treatments.

(a) Western blots showing MAP3K8, P-MEK and MEK protein levels in seven different mouse models of patient-derived xenograft (PDX). One representative tumour is shown for each model. Actin is used as an internal control for protein loading. (b) Scatter plots of MAP3K8 protein levels in tumours from the seven PDX mouse models studied, as assessed by densitometry analysis of western blots. PDX models with high MAP3K8 protein levels (PDX1,3,4,5) are in black, while PDX models with low- or intermediate-MAP3K8 protein levels (PDX2,6,7) are in light or dark grey, respectively. (c) Correlation plot between P-MEK/MEK and MAP3K8 protein levels in tumours from the seven PDX models. (d) Western blots showing MAP3K8, P-MEK and MEK protein levels in tumours derived from PDX1,5 and PDX2,6 with high- and low-MAP3K8 protein levels, respectively. Actin is used as an internal control for protein loading. (e) Scatter plots of MAP3K8 (left) and P-MEK (right) protein levels, as assessed by densitometry analysis of the western blots shown in a in PDX with high- (PDX1,5, black) or low- (PDX2,6, grey) MAP3K8 protein levels (N⩾4 tumours per group). (f) Correlation between P-MEK and MAP3K8 protein levels in tumours derived from PDX1,2,5,6 models. (g,h,i,j) Relative tumour volume over time of PDX models exhibiting either high- (PDX1,5) (g,i) or low- (PDX2,6) (h,j) MAP3K8 protein levels. Mice were either untreated (Ctrl, black lines) or subjected to per os treatment with MEK inhibitors, including AZD6244 and MEK162 (grey lines) (N⩾6 mice per group). (k) Scatter plot of tumour growth inhibition (TGI) in AZD6244- and MEK162-treated groups, as compared with the control group in high- (PDX1,PDX5) or low- (PDX2,PDX6) MAP3K8 PDX models (N⩾6 tumours per group). (l) Bar plot of TGI per mouse in PDX1 (high-MAP3K8 model) following conventional therapy (carboplatin+paclitaxel) alone or in combination with MEK inhibitor (carboplatin+paclitaxel+MEK162) (N⩾8 mice per group). In c and f, correlation coefficients σ and P values are based on Spearman’s rank correlation test. In e,g and h–l, P values are based on the Student’s t-test. Data are shown as mean±s.e.m. *P≤0.05 and **P≤0.005. a.u., arbitrary unit.