EGFR inhibition in non-small cell lung cancer: current evidence and future directions

The epidermal growth factor receptor (EGFR), a 170 kD transmembrane protein consisted of a N-terminus extracellular ligand-binding site, a hydrophobic transmembrane domain, and a C-terminus intracellular region with tyrosine kinase activity, is the first of the ErbB family of receptor tyrosine kinases (RTKs) [1,2]. The other members include ErbB2 (HER2/neu), ErbB3 (HER3), and ErbB4 (HER4). These receptors trigger downstream signaling pathways which lead to multilayered, complex interactions resulting in combinatorial responses. Disruption of these pathways was found to cause malignant transformation [1]. The EGFR is activated through ligand-induced homo or heterodimerization of the receptor with other receptors of the ErbB family under physiologic conditions, but can also be activated due to receptor over-expression, increase of EGFR gene copy number, and activating mutations [3]. EGFR activation has been shown to play a key role in tumor cell proliferation, apoptosis, tumor-induced angiogenesis, metastasis, and DNA damage repair after cytotoxic insults [1,4]. This makes it an attractive target in cancer therapy; and its inhibition a strategy for augmentation of the efficacy of chemotherapy and radiotherapy. Since the initial discovery of the EGFR in 1962, a class of antibodies blocking the EGFR’s extra-cellular ligand binding site to prevent receptor activation, and to down-regulate EGFR expression at the cell surface through antibody mediated receptor dimerization; and low molecular weight tyrosine kinase inhibitors, which competes with ATP to bind to the intra-cellular tyrosine kinase portion of the receptor to abrogate the receptor’s catalytic activity to activate downstream signaling pathways, have been developed [1,4-6]. Among them, reversible small molecule (SM) tyrosine kinase inhibitors (TKIs), Gefitinib and Erlotinib, and the mono-clonal antibody (mAb) against EGFR, Cetuximab, have been the most thoroughly investigated. Both Cetuximab and the SM TKIs have