(467f) Mutation Location Impacts the Efficacy of Tyrosine Kinase Inhibitors on Epidermal Growth Factor Receptor Proteins: Insights from Molecular Dynamics Calculations

Epidermal growth factor receptor (EGFR) protein is a well-known target for non-small cell lung cancer (NSCLC). It has been shown that the location of the mutation in the kinase domain dictates the efficacy of the tyrosine kinase inhibitors (TKIs). It is necessary to understand the impact of the mutation on the structure of the protein and the mechanism of action of the drugs in presence of the mutations, to overcome TKI resistance. In this work, we use molecular dynamics simulations and advanced sampling techniques to predict the effect of mutation on the structure of the EGFR protein and determine the drug binding affinity of different TKIs with the wild type and mutated protein. We examine several exon 19 single and compound mutations and exon 20 insertion mutations and show the impact of the nature and location of the insertion mutation on first, second, and third generation TKIs. We show that our predictions are consistent with experimental data and clinical studies, providing atomistic insights into the mechanisms of TKI binding to EGFR.