We also investigated the growth response of these cancer cell lines to treatment with PI3K and MAPKK inhibitors and found that these sellectchem were less effective contain compared to afatinib and NVP AEW541. Since the selleck screening library Inhibitors,Modulators,Libraries IC50 values of these inhibitors for Inhibitors,Modulators,Libraries their respective targets are below 2 uM, our results suggest that the panel of pancreatic cancer cell lines used in this study is highly re sistant to inhibition of PI3K and MAPKK. We next assessed the anti tumour activity of these agents when used in combination. There was Inhibitors,Modulators,Libraries no im provement in anti tumour activity when NVP AEW541 was used in combination with mAb ICR62. Treatment with a combination of gemcitabine and NVP AEW541 resulted in synergistic growth inhib ition only in PANC1 cell line.

Interestingly, treatment with a combination of NVP AEW541 and afatinib was found to be superior, leading to a synergistic growth inhibition of all pancreatic cancer cells Inhibitors,Modulators,Libraries with the exception Inhibitors,Modulators,Libraries of PT45 which was Inhibitors,Modulators,Libraries the most resistance Inhibitors,Modulators,Libraries cell line to treatment with NVP AEW541. Synergism following treatment with Inhibitors,Modulators,Libraries a combination of NVP AEW541 and HER inhibitors has previ ously been reported in studies involving breast and colo rectal cancer cells. Investigation of the effect of IGF IR ligands and HER ligands EGF and NRG 1 on the downstream signaling in BxPc3 cells revealed that EGF primarily induces phosphorylation of MAPK Inhibitors,Modulators,Libraries while IGF IR ligands activate predominantly the PI3K/AKT pathway.

The activation of different pathways Inhibitors,Modulators,Libraries by the HER family and IGF IR systems could explain the syner gistic effect exhibited by the combination of pan HER blocker afatinib and IGF IR inhibitor in this cell line.

In op timal growth conditions afatinib Inhibitors,Modulators,Libraries was more potent at down regulating both AKT and MAPK basal phosphorylation levels while NVP AEW541 Inhibitors,Modulators,Libraries downregulated pAKT but had no Inhibitors,Modulators,Libraries effect on pMAPK basal levels in BxPc3 cells. However, even Inhibitors,Modulators,Libraries though afatinib was more effective at downregulating Inhibitors,Modulators,Libraries pAKT than NVP AEW541, only the combination of NVP AEW541 with afatinib led to complete loss of AKT phosphorylation.

In order p53/MDM2 interaction to determine whether the diverse activation of AKT and MAPK pathways by EGFR and IGF IR acti vation could explain the synergism exhibited by the same combination in the rest of the cell lines we determined the selleck Tipifarnib effect of EGF and IGF on the phosphor ylation of AKT and MAPK in all cell lines included in this study.

Interestingly, with the exception of FA6 cells, the pattern of AKT and MAPK selleck bio activation in all the other pancreatic cells was found to be similar to BxPc3 cells . EGF predominantly led to the activation of MAPK whereas IGF treatment increased mainly the phosphorylation of AKT but had low or no effect on phosphorylation of MAPK.