(535d) Kinetic Model of EGF Receptor Activation and Inhibition

The binding of ligand to the epidermal growth factor receptor (EGFR) promotes receptor dimerization, activation of kinase activity, and phosphorylation of tyrosine residues that serve as docking sites for intracellular signaling adapters. Because EGFR is over-expressed in many cancers, antibodies and small-molecule therapeutics have been developed to inhibit EGFR in the clinical setting. Here, we develop an ordinary differential equation based model of EGFR activation and inhibition in order to gain quantitative understanding of how multiple receptor-level phenomena affect the efficacy of EGFR-directed therapeutics. Standard models of enzyme kinetics and inhibition (e.g., Cheng-Prusoff) are insufficient for this purpose because they neglect key phenomena involved in EGFR activation (e.g., receptor dimerization). This fact is made evident by the finding that the EGFR system can only be forced to mimic the behavior of standard models under extreme limiting conditions that are not representative of cellular or in vitro experimental settings. Our analysis focuses mainly on the effects of alterations in receptor trafficking, receptor expression level, and phosphatase activity in modulating the inhibitory capacity of small-molecule drugs. Perturbations along each of these axes characteristic of what is observed in EGFR-mediated cancers is predicted to significantly alter the ability of EGFR-directed small molecules to inhibit EGFR phosphorylation. Significant effort is also dedicated to the analysis of the previously reported coupling between EGFR internalization and accessibility to phosphatases. Contrary to other reports, our analysis suggests that EGFR is in fact accessible to phosphatases while still at the plasma membrane. We will present experimental data in support of this notion as well and interpret that data using the model. Overall, the results of this work suggest that perturbations to multiple receptor-level phenomena that occur in EGFR-mediated cancers may significantly alter the inhibitory capacity of EGFR-directed therapeutic molecules.