The protein encoded by EGFR (epidermal growth factor receptor) exists on the cell surface and is activated by binding of its specific ligands, including epidermal growth factor and transforming growth factor α (TGFα). Upon activation by its growth factor ligands, EGFR undergoes a transition from an inactive monomeric form to an active homodimer. In addition to forming homodimers after ligand binding, EGFR may pair with another member of the ErbB receptor family, such as ErbB2/Her2/neu, to create an activated heterodimer.
EGFR dimerization stimulates its intrinsic intracellular protein-tyrosine kinase activity. As a result, autophosphorylation of several tyrosine residues in the C-terminal domain of EGFR occurs. This autophosphorylation elicits downstream activation and signaling by several other proteins. These downstream signaling proteins initiate several signal transduction cascades, principally the MAPK, Akt and JNK pathways, thus modulating phenotypes such as cell migration, adhesion, and proliferation. Activation of the receptor is important for the innate immune response in human skin.
Somatic EGFR mutations have been associated mainly with lung cancer. They have also been observed in a small minority (<7%) of other tumors, such as those of adrenal glands, CNS, prostate, thyroid…
Mutations are mostly substitutions (about 50%) and deletions (about 33%). There are no fusion mutations.
Many mutation events occur in a region corresponding to amino acids 700-850. There is a substitution hot spot at amino acid 858. Complex mutation events have a hot spot at amino acids 746-750.
The rational design of anti-EGFR small-molecule tyrosine kinase inhibitors (TKIs) led to the development of gefitinib. Other TKIs have been introduced, such as erlotinib. Other anti-EGFR compounds are monoclonal antibodies cetuximab and panitumumab. EGFR inhibitors have shown highly promising activity in the clinic, which has led to EGFR being one of the most studied molecular targets in clinical oncology. Coincident with this interest in targeting EGFR was the identification of intrinsic and acquired resistance to EGFR inhibitors (Wheeler DL et al. 2010).
lapatinib, a dual tyrosine kinase inhibitor of EGFR and HER-2 receptors, is clinically effective against HER-2-overexpressing metastatic breast cancer and could be a clinically useful agent for the treatment of lung cancer (Diaz R. et al. 2010).
Understanding resistance to EGFR inhibitors-impact on future treatment strategies. Wheeler DL, Dunn EF, Harari PM. Nat Rev Clin Oncol. 2010 Sep;7(9):493-507.
The emerging role of epidermal growth factor receptor (EGFR) inhibitors in first-line treatment for patients with advanced non-small cell lung cancer positive for EGFR mutations. Okamoto I, Mitsudomi T, Nakagawa K, Fukuoka M. Ther Adv Med Oncol. 2010 Sep;2(5):301-7.
Antitumor and antiangiogenic effect of the dual EGFR and HER-2 tyrosine kinase inhibitor lapatinib in a lung cancer model. Diaz R, Nguewa PA, Parrondo R, Perez-Stable C, Manrique I, Redrado M, Catena R, Collantes M, Peñuelas I, Díaz-González JA, Calvo A. BMC Cancer. 2010 May 11;10:188.