Epidermal Growth Factor Receptor-Targeted Therapies

Abstract

The epidermal growth factor receptor (EGFR) has been implicated in the progression and maintenance of various solid tumors. Efforts in understanding EGFR biology and related signaling cascades have lead to the development of anti-EGFR agents. The two main approaches of inhibition that have been ­studied most extensively are monoclonal antibodies and tyrosine kinase inhibitors. Despite clear evidence of antitumor activity in preclinical models, only a subset of cancer patients show clinical responses to EGFR inhibitors. Additionally, a majority of patients who demonstrate an initial response become refractory to continued therapy. Possible mechanisms of resistance to anti-EGFR therapy include EGFR overexpression, redundant parallel growth factor receptors, ErbB family heterodimerization, EGFR mutations, the presence of nuclear EGFR, and constitutive activation of downstream signaling mediators. Understanding the molecular mechanisms of resistance is critical in the development of combination therapies to target resistance pathways and improve clinical outcomes. Furthermore, idenepsication of biomarkers that indicate sensitivity or resistance to anti-EGFR therapy will enable the selection of patients who are more likely to benefit from EGFR-targeted therapy.

The epidermal growth factor receptor (EGFR) tyrosine kinase plays an important role in the progression of many human cancers, and molecular inhibitors that target EGFR have been extensively investigated for anti-cancer therapy. Anti-EGFR agents have shown promising activity in clinical trials and are now Food and Drug Administration (FDA)-approved for use in selected groups of cancer patients. However, most patients ultimately develop resistance to these agents. In this chapter, we will discuss the therapeutic potential of targeting EGFR, the effects of using EGFR inhibitors, and possible mechanisms of resistance to EGFR inhibitors.