Prediction Of The Impact Of Genetic Variability On Drug Sensitivity For Clinically Relevant EGFR Mutations

Abstract

Mutations in the kinase domain of the Epidermal Growth Factor Receptor (EGFR) can be drivers of cancer and also trigger drug resistance in patients under chemotherapy treatment based on kinase inhibitors use. A priori knowledge of the impact of EGFR variants on drug sensitivity would help to optimize chemotherapy and to design new drugs effective against resistant variants. To this end, we have explored a variety of in silico methods, from sequencebased to ’state-of-the-art‘ atomistic simulations. We did not find any sequence signal that can provide clues on when a drug-related mutation appears and what will be the impact in drug activity. Low-level simulation methods provide limited qualitative information on regions where mutations are likely to produce alterations in drug activity and can predict around 70% of the impact of mutations on drug efficiency. High-level simulations based on non-equilibrium alchemical free energy calculations show predictive power.