Effectively inhibited by ICQN lines IkB Signaling in the EGFR mutated cells. However, it remained the Lebensf Ability and colony-forming ability F Of anchorage independent Independent cells YOUR BIDDING unchangedalmost inhibited IGF-1R and IGF-induced Akt phosphorylation in H596 cells. Similar results were found in A549 cells, indicating that ICQN effective in blocking IGF-1R signaling in NSCLC cells is independent Ngig from the point of Ras mutation K. These results indicate that the mechanism of reduced K-ras mutation the sensitivity of NSCLC cells to ICQN independent is ngig of the ligand-induced phosphorylation of the IGF 1R. Active Ras mutant K 1R/Akt IGF signaling, but leads to resistance to IGF 1R/IR TKI Given the strong positive correlation between IGF 1R activation and K ras mutation in human NSCLC TMA and inverse correlation between the sensitivity and ICQN K ras mutation in NSCLC cell lines, we also have the r the K mutation in the Ras signaling pathway of IGF 1R and sensitivity ICQN in H226B and H596 cells examined, wherein the protein fluorescence mutant Ras-green or K had been transduced by retroviral infection. K-ras H226B cells showed an hour Here PlGF 1R and IGF 1R pAkt and lower than those expressing GFP-cells H226B. We have also observed that cells K H226B Ras produces more IGF-1, is that H226B cells, GFP. To further characterize the molecular consequences of mutated ras K loan St, we conducted a series of reversed-phase proteins. Unsupervised hierarchical clustering analysis showed that PI3K pathways / Akt and Ras / MAPK were activated KRAS. Although the treatment reduces ICQN 1R/IR and PlGF pAkt levels in both cell lines, the phosphorylation of downstream mediators of Akt confinement, Lich PS6 and pGSK, was effectively prevented by treatment ICQN in cells H226B but not GFP inH226B K ras cells. Furthermore, H226B, and H596 cells were KK RAS far less sensitive to a treatment that controlled ICQN cells Goods, suggesting that IGF-1R signal transduction by the mutated Ras-K obtained Is ht, however, K Ras mutation, the sensitivity of NSCLC cells raises through the activation of ICQN downstreamsignaling confinement, P70S6K Lich. Targeting MEK is best replaced RESISTANCE Of mutated ras K-cells to IGF-1R TKI Because p70S6K known that the MEK / ERK, 26 which are activated in fa k Can be activated K constitutive Ras mutation, we have determined whether the inactivation of MEK would again the antitumor effect of ICQN or OSI 906th We found that cotargeting MEK or with a small molecule MEK inhibitor or with adenovirus dominant negative form of MEK, significantly increased Ht the effect of ICQN the Zelllebensf Ability and verankerungsunabh Independent Koloniebildungsf Ability of lines representative in Ras mutant K- resistant cells. In addition, the percentage of apoptotic cells increased fa Ht Is significant in the combined treatment. These results suggest that inactivation of the apoptotic activity of MEK t in NSCLC cells expressing mutant Ras ICQN K obtained Ht. We finally have the combined effects of OSI-906 and U0126 studied in vivo. Mice that were treated with vehicle or OSI-906 alone Similar K H226B tumor growth in Ras. Pharmacological inhibition of MEK by U0126 administration obtained Hte significant effect on tumor growth by OSI 906. On day 8 after the first dose, the mean tumor volume in mice M Who have again U combined 906 and OSI.