A 4h of treatment 72h of treatment 1mM PI3Kbi - + - - - + + + + + - +

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A 4h of treatment 72h of treatment 1mM PI3Kbi - + - - - + + + + + - + - - - + + + + + untreated 1mM PI3Kai - - + - - + - - + - - - + - - + - - + - 1mM IGF1Ri - - - + - - + - - + - - - + - - + - - + 0.1mM MEKi - - - - + - - + + + - - - - + - - + + + a-pAkt S473 a-pAkt T308 a-Akt a-pPRAS40 T246 a-pNDRG1 T346 a-pERK1/2 T202/Y204 a-ERK1/2 a-pS6 S235/236 a-pS6 S240/244 a-S6 a-tubulin 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 B 2h of treatment 72h of treatment 1mM PI3Kbi - + - - - + + + + + - + - - - + + + + + untreated 1mM PI3Kai - - + - - + - - + - - - + - - + - - + - 0.01mM IGF1Ri - - - + - - + - - + - - - + - - + - - + 0.1mM MEKi - - - - + - - + + + - - - - + - - + + + a-pAkt S473 a-pAkt T308 a-Akt a-pPRAS40 T246 a-pNDRG1 T346 a-pERK1/2 T202/Y204 a-ERK1/2 a-pS6 S235/236 a-pS6 S240/244 a-S6 a-tubulin 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Suppl. Figure 6: Concomitant inhibition of PI3Kb, IGF1R and MAPK signaling are leading to full long-term pathway blockade. A) +B) Effects of treatment with the indicated inhibitors as single-agents or in combination on WM-266-4 (A) or RVH-421 (B) were evaluated by immunoblotting using phospho-specific or total target protein antibodies. PI3Kbi=rac-KIN-193, PI3Kai=BYL719, IGF1Ri (A)=AEW541, IGF1Ri (B)=Figitumumab-like antibody, MEKi=MEK162