Targeting EGFR

  • EGFR TKIs are approved for treatment in NSCLC. These inhibitors are either competitive inhibitors of ATP binding sites inhibitors, preventing phosphorylation of the tyrosine kinase domains of EGFR.

First-Generation TKIs

  • First-generation EGFR TKIs included gefitinib and erlotinib. They are reversible competitive inhibitors of ATP binding.
  • Gefitinib and erlotinib are both first-line treatment of metastatic NSCLC with EGFR exon 19 deletion or L858R substitution mutation.

Second-Generation TKIs

  • Second-generation EGFR TKIs are competitive irreversible inhibitors of ATP binding. They circumvent acquired drug resistance seen with the first-generation inhibitors.
  • In 2013, Afatinib was approved xon 19 deletion mutations. Afatinib also blocks dimerization of EGFR with HER2 and is more effective in inhibiting EGFR kinase activity than the first-generation inhibitors. Afatinib exhibits activity against the EGFR T790M resistance mutation as well.
Other topics in Molecular Targets and Pathways