Structural insight into the binding mechanism of ATP to EGFR and L858R, and T790M and L858R/T790 mutants.

The L858R mutation in EGFR is particularly responsive to small tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib. This efficacy decreases due to drug resistance conferred by a second mutation, T790M, which subsequently produces a double mutant, L858R/T790M. Although this resistance was initially attributed to steric blocking by the T790M mutation, experimental studies have demonstrated that differences in the binding affinities of TKIs to T790M and L858R/T790M mutants are more a result of the increased sensitivity of these mutants to ATP than to a decrease in the affinity to TKIs.