To investigate the mechanism by which K Ras mutation rescues NSCLC cells from PQIP treatment, we examined the PQIP induced antiproliferative activities H460 and H157 cells after mut K Ras was knocked out by transfection with specific siRNA against K Ras. After K Ras expression was silenced by transfection ALK inhibitor with specific siRNA, showing an essential role of mut K Ras in mediating PQIP weight within the NSCLC cell lines both H460 and H157 cells unmasked a notably improved PQIP sensitivity. We next examined the consequences of PQIP on IGF 1R signaling in H596 cells, which carry A549 cells, and wt K Ras, which carry mut K Ras. We found that PQIP treatment at 1 uM almost completely inhibited Akt phosphorylation and IGF induced IGF 1R in cells. Similar results were found in A549 cells, indicating that PQIP works well in blocking IGF 1R signaling in NSCLC cells regardless of E Ras mutation status. These results indicate that the mechanism through which KRas mutation decreases NSCLC cell sensitivity to PQIP is in addition to the ligandinduced phosphorylation of IGF 1R. Mut K Ras Activates IGF 1R/Akt Signaling but Leads to Resistance Messenger RNA to IGF 1R/IR TKI Given the strong positive correlation between IGF 1R initial and K Ras mutation within the individual NSCLC TMA and the inverse correlation between PQIP sensitivity and K Ras mutation in NSCLC mobile lines, we further examined the position of K Ras mutation within the IGF 1R pathway and PQIP sensitivity in H226B and H596 cells in which GFP or mut K Ras was transduced by retroviral infection. H226B K Ras cells showed higher levels of pAkt and pIGF 1R and lower levels of IGF 1R than those in H226B GFP cells. enzalutamide We also noticed that H226B K Ras cells produced more IGF 1 than H226B GFP cells did. To characterize further molecular sequelae activated by mut K Ras, we performed a reverse phase protein array Unsupervised hierarchical clustering analyses demonstrated the Ras/MAPK and PI3K/Akt pathways were activated by mut K Ras. While PQIP treatment reduced pAkt and pIGF 1R/IR levels in both cell lines, phosphorylation of the downstream mediators of Akt, including pS6, and pGSK, was successfully inhibited by PQIP treatment in H226B GFP cells but not in H226B K Ras cells. More over, H226B K Ras and H596 K Ras cells were significantly less sensitive and painful to PQIP treatment compared to control cells were, indicating that IGF 1R signaling is enhanced by mut K Ras, nevertheless, K Ras mutation abrogates NSCLC cell sensitivity to PQIP by causing downstream signaling, including p70S6K Targeting MEK Overrides the Resistance of mut K Ras Cells to IGF 1R TKI Because p70S6K is known to be activated by the MEK/Erk pathway,27 which can be constitutively activated by K Ras mutation, we determined whether inactivation of MEK would recover the antitumor effects of PQIP or OSI 906 or with adenovirus expressing the dominant negative kind of MEK, significantly enhanced the effects of PQIP on cell viability and anchorageindependent colony forming ability in representative mut K Ras, resistant cell lines.