Primary external reference:
L858R, a substitution of leucine 858 with arginine, accounts for ~40% of EGFR mutations in the non-small-cell lung cancer. L858R, encoded by exon 21, localizes to the N-terminal portion of the activation loop (A loop) of the kinase domain of EGFR. By locking the EGFR in its active conformation, L858R mutation results in constitutive catalytic activity of EGFR which is ~50-fold higher than the activity of the wild-type enzyme (Yun et al. 2007). The L858R EGFR mutant is inhibited by binding of small EGFR-specific tyrosine kinase inhibitors from the 4-anilinoquinazoline group, erlotinib and gefitinib, as well as the pyrrolopyrimidine compound AEE788. Gefitinib is ~100-fold more potent against the L858R mutant than against the wild-type EGFR kinase (Yun et al. 2007). Erlotinib (Pao et al. 2004) and AEE788 (Yun et al. 2007) are also more efficient in inhibiting the L858R mutant than the wild-type EGFR.