Insight into the impact of EGFR L792Y/F/H mutations on sensitivity to osimertinib: an in silico study

Osimertinib is the first third-generation epithelial growth factor receptor (EGFR) inhibitor, and it has been approved as a first-line medication for metastatic non-small cell lung cancer (NSCLC). Recently, the clinical use of osimertinib has revealed the emergence of new mutations, L792F, L792Y, and L792H (L792X), which endow lung cancer cells with the ability to escape drug inhibition. However, the binding mode between osimertinib and these mutants as well as the resistance mechanisms remains poorly understood. Here, we investigated the inhibitory process associated with EGFR T790M (sensitive to osimertinib) and EGFR T790M/L792X (resistant to osimertinib) by modeling the recognition step and the dissociation step using an integrated computational approach. Using molecular mechanics/generalized Born surface area (MM/GBSA) free energy calculations, the results indicated that the L792X mutation from a hydrophobic amino acid to a hydrophilic amino acid might be the main reason for the difference in binding free energy of each mutant. Per-residue binding free energy decomposition analysis showed that the binding energy contribution of residues Met-793 and Gly-796, and the mutant residues, is most strongly affected by the L792X mutation. Moreover, umbrella sampling (US) simulations revealed that the resistance effect conferred by the L792X mutation is mainly caused by a decreased interaction between osimertinib and the hinge region of EGFR. Our research results provided new insights into drug resistance caused by the L792X mutation and gave valuable guidance for the development of more effective inhibitors.