ABSTRACT
INTRODUCTION e cancer phenotype may be viewed as a pathological dysregulation of cellular signals that control growth, survival, motility, cell-cell connectivity, and DNA synthesis and repair (Hanahan and Weinberg 2000). Generally speaking, the sources of dysregulation are an accumulated set of mutations that produce altered gene products. e interaction of these
CONTENTS Introduction 31 Model 33
Constructing Mechanistic Models of Oncogenic Signaling 35 Providing Alternate Parameterization through Docking Simulations 38 Resolving the Structure of Mutant Oncoproteins through Molecular Dynamics 38
Results 39 Activation of Wild-Type EGFRTK and L834R Mutant RTK 39 Ligand and Substrate Binding Anities for EGFRTK 40 Dierential Signaling through EGFRTK 41
Discussion 41 Acknowledgments 43 References 43
mutant oncoproteins with normal host signaling mechanisms perturbs proper signaling and confers the oncogenic behavior. For example, mutations aecting the catalytic activity, binding specicity, translation e- ciency, or rate of degradation of an enzyme involved in DNA repair can predispose a cell to genomic instability by allowing replication of damaged genomic sequence (Zhivotovsky and Kroemer 2004). e specic identities and combinations of these cancer-causing mutations are known to vary considerably according to tissue and cell type and are strongly interdependent on the cellular/tumor microenvironment (Sjoblom, Jones, et al. 2006). In light of these complexities, mathematical models of cellular signaling networks have become indispensable tools for explaining oncogenic behaviors, predicting resistance mechanisms, and designing molecular therapies to attenuate defective signaling.
