EGFR Inhibitors

EGFR Inhibitors Mechanism of Action
Erlotinib, Gefitinib, Vandetanib Inhibits EGFR-driven cell proliferation and survival by inhibiting the EGFR kinase activity
Cetuximab, Panitumumab Anti-EGFR antibody blocks EGF-dependent proliferation and survival by interfering with EGFR activation
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  1. Mutations in the EGFR gene lead to activation of the kinase function so that signaling occurs without binding of the ligand (e.g., EGF). Increased copy number can result in higher expression of the EGFR protein and increased tumor cell dependency on EGFR signaling.
  2. EGFR signaling turns on both the KRAS and PI3K pathways, leading to increased tumor cell growth and survival.
  3. Mutations in KRAS that result in constitutive GTPase activity uncouple the RAS pathway from its dependency on EGFR so that cell growth is driven without EGFR activity.
  4. Mutations in the BRAF kinase render it independent of RAS regulation so that cell growth is driven without RAS.
  5. PTEN acts as a negative regulator of PI3K pathway activity. Loss of PTEN protein or function results in unchecked activity of this pathway and cell growth in the absence of stimulation from upstream growth factors, such as EGF.

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Green squares, sensitivity markers. Red squares, resistance markers