Progress of EGFR Mutation and EGFR-targeted Therapy

The epidermal growth factor receptor(EGFR) belongs to the super-family of receptor tyrosine kinase and is expressed in many malignancies. Upon their ligand-induced dimerization and conformational change, it initiates activation of intracellular tyrosine kinase and a vast array of cell signaling pathways. The cascade of intracellular activation results in cell proliferation, invasion, metastasis and decreased apoptosis. EGFR represents a critical player in many types of malignancies and becomes a natural goal of the targeted therapy. Both monoclonal antibodies and tyrosine kinase inhibitors (TKIs), such as erlotinib and gefitinib, have already entered clinical application. Clinical trials have shown that only 10%-30% of patients responded to the TKIs treatment. Further studies have found that some mutations within the kinase domain activated the kinase and conferred sensitivity to the treatments. The detection of mutations will likely predict the sensitive patients and improve the outcome of current EGFR-targeted therapy. During the treatment, the vast majority of responders developed acquired resistance. Roughly half the mutant EGFR cases with acquired resistance to TKIs have a secondary mutation (T790M) that reduces drug affinity to the kinase target. Many molecules on the downstream of EGFR or by-pass activating pathways also contribute to the drug resistance. In the future, patient-specific treatment approach will have to consider not only the EGFR itself, but also genes on downstream and compensatory pathways, such as PI3K, K-RAS, BRAF, MET and PTEN.