EGFR Signaling

The epidermal growth factor receptor (EGFR) protein belongs to the the erbB receptor tyrosine kinase (TK) family and is a transmembrane glycoprotein that transduces extracellular signals to the nucleus when activated upon ligand binding. EGFR is expressed on the surface of the majority of normal cells. The receptor consists of three regions, the extracellular ligand binding region, the intracellular region with TK activity and a transmembrane region. Figure 1 shows a schematic of the EGFR protein. Both the extra and intra-cellular domains are divided into sub-domains as shown in Figure 1. The ligands binding to EGFR include, EGF, transforming growth factor-a (TGF-a), am-phiregulin (AR), Heparin-binding EGF-like growth factor (HB-EGF), and betacellulin (BTC). Tyrosine kinase activity plays a key role in regulating cell proliferation and differentiation.

Over expression of EGFR has been shown to promote development and progression of a number of cancers including breast, colorectal, head and neck, bladder and lung. However, the precise mechanism for EGFR regulation of cancer remains elusive.

Several anti-EGFR drugs have been developed and have shown variable response rates in NSCLC patients. The most common anti-EGFR inhibitors are gefitinib and erlotinib, both of which are prescribed as second-line treatment after chemotherapy. Both drugs are quinazalone-based and are reversible inhibitors of the tyrosine kinase domain. Retrospective studies based on NSCLC patients treated with gefitinib or erlotinib have shown that a subset of patients respond much more effectively to the drugs than other patients. The primary reason for this distinction has been attributed to the presence of somatic mutations in the kinase domain of EGFR.

These mutations have been shown to increase the sensitivity of tumor cells to gefitinib and erlotinib in vitro and may explain the variability in clinical response among patients. Overall, the frequency of EGFR mutations in NSCLC is 5-20%, depending on the population being studied. In N.America, the frequency is estimated to be 10%. The response rate for patients with activating EGFR mutations is approximately 75%. The classical activating mutations that are most commonly found in responsive patients (~90%) are: Exon 19 deletions and Exon 21 L858R mutations in the Kinase domain.

Another subset of patients treated with gefitinib or erlotinib were initially responsive to the drug, but later developed secondary mutations in the kinase domain that conferred resistance. The inactivating mutations that are most commonly found, include point mutations in the tyrosine kinase domain (T790M), MET amplification and PIK3CA mutations. The T790M mutation is responsible for over 50% of the resistance cases resulting from EGFR TKIs. MET amplification has been shown to induce resistance to EGFR TKIs by activating the HER3 pathway and is responsible for 5-20% of cases of acquired resistance. Mutations in the catalytic subunit of the PI3K protein have also been shown to confer resistance to EGFR TKIs and are responsible for 4% of such cases in NSCLC patients. Other less common mutations are insertion point mutations in exon 20 of the EGFR gene, which include D770_N771 (ins NPG), D770_(ins SVQ) and D770_(ins G) N771T.

Figure 1- Schematic representation of the EGFR protein and its domains.

Image adapted from Voldborg BR et al., 1997.

Figure 2 - Cartoon depiction of the EGFR protein on the cell surface membrane and its interaction with targeted drugs. Downstream effects of EGFR are also highlighted. Image adapted from Mukohara T, et al. 2005.