This result indicates that synergism is produced by the dual inhibition of the step of EGFR phosphorylation which both Mig6 and gefitinib inhibit and the step of binding of EGFR to Shc which Mig6 alone inhibits. Discussion Overexpression or mutation of EGFR has been observed in lung cancers, selleck bio and these molecular changes affect the prognosis and treatment sensitivity of patients. Those abnormalities could cause changes in overall titers of signaling networks at the molecular, the cellular, and even the individual levels. Mathematical model is helpful for understanding of the mechanical aspects of interconnected signaling network and predict ing input output behaviors in the pathway. However, it is often very difficult to explain the variation of reac tants in signal transduction pathway using a single uni fied mathematical model.

In this paper, Inhibitors,Modulators,Libraries we attempted to build such a unified model that could uncover the cell specific regulatory mechanisms produced by overexpres sion and Inhibitors,Modulators,Libraries mutation of the EGFR and the association with gefitinib sensitivity. The model used in this paper successfully reproduced the experimental observations concerning the activation of the key proteins in the pathway and discriminated the roles of Mig6 and Cbl in gefitinib sensitivity. The model was based on kinetic equations, and most of the parameters for these equations were common for all models. The differences in the parameters were confined to specific steps and proteins EGFR overexpression, inhibitory effects caused by Mig6, and Cbl overexpres sion leading to the degradation of EGFR.

Inhibitors,Modulators,Libraries Our results revealed that the effectiveness of gefitinib in cells is largely affected by not only on its direct binding affinity with EGFR but also on the presence of an addi tional molecule, Mig6. According to recent reports, the sensitivity to kinase inhibition reflects intrinsic differ ences in the binding affinity of the EGFR mutants such as L858R, G719S, and exon19 deletions. Yun et al showed that gefitinib directly binds more tightly to the L858R mutant than to the wild type EGFR in vitro, while Fabian et al indicated that EGFR with gefitinib sensitive mutations does not differ from wild type EGFR in terms of gefitinib binding affinity. This would suggest that the stronger interaction of the mutated EGFRs with gefitinib may not be the only one mechanism for the good clinical response to gefitinib in NSCLC.

This inconsistency Inhibitors,Modulators,Libraries in previous reports suggested to us that unknown factors may play an important role in gefitinib Inhibitors,Modulators,Libraries sensitivity. The gefitinib dose response study showed that the difference in the phosphorylation levels of the downstream proteins http://www.selleckchem.com/products/CHIR-258.html inhibited by gefitinib is large between H1299EGFR WT and H1299L858R cells, whereas the difference in the upstream proteins is small.