Understanding Resistance to EGFR Inhibitors—Impact on Future Treatment Strategies

Deric L. Wheeler; Emily F. Dunn; Paul M. Harari

In This Article

Abstract and Introduction


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.


In 1962, Stanley Cohen isolated and characterized a salivary gland protein that induced eye-lid opening and tooth eruption in newborn mice.[1] Further experimentation showed that this protein could stimulate the proliferation of epithelial cells and was thus named epidermal growth factor (EGF).[2] It was not until a decade later, when Graham Carpenter performed experiments using 125iodine-labeled EGF, that the presence of specific binding receptors for EGF on target cells were identified.[3] Subsequently, Carpenter and coworkers identified the EGF receptor (EGFR) as a 170 kDa membrane protein that increased the incorporation of 32phosphorus into EGFR in response to EGF treatment of A431 epidermoid carcinoma cells.[4] A group of collaborators isolated, cloned and characterized the sequence of human EGFR from normal placental cells and A431 tumor cells in 1984.[5] Over the same time period, it was discovered that modification of proteins by phosphorylation on tyrosine residues might be a critical step in tumorigenesis.[6,7] Shortly after these discoveries, EGFR was recognized as a receptor tyrosine kinase (RTK). This effort over two decades led to the identification of the prototypical RTK and its ligand. The discovery of EGFR as an RTK contributed to pivotal studies that have advanced our understanding of RTK activation and phosphorylation, and resulted in the elucidation of EGFR regulation of downstream signaling via PLC/PKC and RAS/RAF/MEK/ERK pathways.[8,9]

During the 1980s, several reports described the overexpression of EGFR in a variety of epithelial tumors, which supported the hypothesis that dysregulated EGFR expression and signaling may have a critical role in the etiology of human cancers.[5,10–14] These findings led to investigations to target the receptor with an antibody directed against the extracellular domain of EGFR.[15] Mendelsohn and colleagues developed a series of anti-EGFR monoclonal antibodies, including mAb225 (C225) and mAb528. The mAb225 showed promising antitumor activity in culture and in mouse xenograft models, which subsequently led to its development as a clinical agent.[15,16] FDA approval was given in 2004 for its use in colorectal cancer. In parallel, the rational design of anti-EGFR small-molecule tyrosine kinase inhibitors (TKIs) came to the fore. The development of these agents was further supported by findings that mutations in the EGFR tyrosine kinase domain led to decreased tyrosine function and downstream signaling.[17–19] The inhibitory action of quinazolines was reported in 1994,[20,21] which was soon followed by the development of gefitinib, the first small-molecule inhibitor targeting EGFR.[22] Gefitinib was approved by the FDA in 2003 for use in non-small-cell lung cancer (NSCLC). EGFR inhibitors have shown highly promising activity in the clinic,[23–30] which has led to EGFR being one of the most studied molecular targets in clinical oncology. Coincident with this interest in targeting EGFR was the identification of intrinsic and acquired resistance to EGFR inhibitors. Indeed, the first report calling for a uniform clinical definition of acquired resistance to EGFR inhibitors was published in January 2010.[31] In this Review, we focus on what is known about resistance to EGFR inhibitors in the preclinical and clinical setting. We also discuss potential methods to overcome resistance to EGFR inhibitors and future strategies to optimize successful integration of EGFR-targeting therapies in oncology.