<p>Resistance mutations in the epidermal growth factor receptor (EGFR), particularly the gatekeeper T790M mutation, pose a major challenge for tyrosine kinase inhibitors in the treatment of non-small cell lung cancer. Previous experimental studies reported that the inhibitor BLU-945 selectively targets EGFR variants (EGFR^L858R, EGFR^L858R/T790M, and EGFR^{L858R/T790M/C797S}) while sparing wild-type EGFR. Here, we dissect the binding mechanisms of BLU-945 with wild-type and mutant EGFR by integrating structural dynamics and conformational landscape analysis. Our results reveal that the T790M mutation introduces a bulky, hydrophobic MET-790, which remodels the ATP-binding pocket and forms a hotspot for strong interactions with BLU-945’s aromatic groups. A compact pocket configuration highly compatible with BLU-945 is stabilized by conformational shifts of the P-loop and αC-helix, which modulate essential residue networks, while MET-790 restricts P-loop flexibility. The resulting pocket conformation creates an ideal environment that enhances BLU-945’s binding affinity to EGFR mutants, consistent with the experimental results. Our findings reveal the molecular basis of BLU-945’s efficacy to provide inhibitor designing strategies for overcoming EGFR-driven drug resistance.</p> Graphical abstract <p></p>