Understanding resistance to EGFR inhibitors—impact on future treatment strategies

EGFR is one of the most studied targets in oncology, and several inhibitors have shown promising results in selected patient populations. However, intrinsic and acquired resistance to these targeted therapies is increasingly recognized. The authors of this Review describe the successful translation of EGFR inhibitors to the clinic, and highlight the mechanisms of resistance to these agents that limit their long-term efficacy. Understanding these processes will allow researchers to develop therapies that overcome resistance and ultimately lead to more successful outcomes. EGFR is a tyrosine kinase that participates in the regulation of cellular homeostasis. Following ligand binding, EGFR stimulates downstream cell signaling cascades that influence cell proliferation, apoptosis, migration, survival and complex processes, including angiogenesis and tumorigenesis. EGFR has been strongly implicated in the biology of human epithelial malignancies, with therapeutic applications in cancers of the colon, head and neck, lung, and pancreas. Accordingly, targeting EGFR has been intensely pursued, with the development of a series of promising molecular inhibitors for use in clinical oncology. As is common in cancer therapy, challenges with respect to treatment resistance emerge over time. This situation is certainly true of EGFR inhibitor therapies, where intrinsic and acquired resistance is now well recognized. In this Review, we provide a brief overview regarding the biology of EGFR, preclinical and clinical development of EGFR inhibitors, and molecular mechanisms that underlie the development of treatment resistance. A greater understanding of the mechanisms that lead to EGFR resistance may provide valuable insights to help design new strategies that will enhance the impact of this promising class of inhibitors for the treatment of cancer.