EGFR Tyrosine Kinase Inhibitor (EGFR-TKI)

EGFR-TKIs are a class of small-molecule drugs that inhibit the intracellular tyrosine kinase domain of the epidermal growth factor receptor (EGFR). They are used primarily in the treatment of cancers with dysregulated EGFR signaling, especially non-small cell lung cancer (NSCLC).

• Compete with ATP for binding to the tyrosine kinase domain of EGFR.
• Prevent autophosphorylation of EGFR and downstream activation of key pathways:
  • RAS/RAF/MEK/ERK → Cell proliferation
  • PI3K/AKT/mTOR → Cell survival
  • JAK/STAT → Immune modulation
• Result: Inhibition of tumor growth, angiogenesis, and metastasis

• First-generation (reversible inhibitors):
  • Erlotinib
  • Gefitinib
• Second-generation (irreversible, broader spectrum):
  • Afatinib
  • Dacomitinib
• Third-generation (T790M mutation-selective):
  • Osimertinib

• Non-small cell lung cancer (NSCLC) with activating EGFR mutations (e.g., exon 19 deletions, L858R)
• Investigational use in glioblastoma and other EGFR-driven tumors

• Secondary mutations (e.g., T790M, C797S)
• Activation of bypass pathways (e.g., MET, HER2)
• Histological transformation (e.g., adenocarcinoma to small-cell)
• Tumor heterogeneity and clonal evolution

• Acneiform rash
• Diarrhea
• Interstitial lung disease (rare but serious)
• Paronychia and dry skin
• Liver enzyme elevation

• EGFR Pathway
• EGFR Inhibitors
• Targeted Therapy
• TKI Resistance Mechanisms
• Osimertinib (Tagrisso)