EGFR Tyrosine Kinase Inhibitor (EGFR-TKI) [Neurosurgery Wiki]

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====== 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)**.

===== Mechanism of Action =====
  * 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**

===== Generations of EGFR-TKIs =====
  * **First-generation** (reversible inhibitors):
    * [[oncology:erlotinib|Erlotinib]]
    * [[oncology:gefitinib|Gefitinib]]
  * **Second-generation** (irreversible, broader spectrum):
    * [[oncology:afatinib|Afatinib]]
    * [[oncology:dacomitinib|Dacomitinib]]
  * **Third-generation** (T790M mutation-selective):
    * [[oncology:osimertinib|Osimertinib]]

===== Clinical Indications =====
  * 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

===== Resistance Mechanisms =====
  * 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

===== Side Effects =====
  * Acneiform rash
  * Diarrhea
  * Interstitial lung disease (rare but serious)
  * Paronychia and dry skin
  * Liver enzyme elevation

===== Related Topics =====
  * [[oncology:egfr|EGFR Pathway]]
  * [[oncology:egfr_inhibitor|EGFR Inhibitors]]
  * [[oncology:targeted_therapy|Targeted Therapy]]
  * [[oncology:tki_resistance|TKI Resistance Mechanisms]]
  * [[oncology:osimertinib|Osimertinib (Tagrisso)]]