EGFR Antagonists in Cancer Treatment

Abstract

C ancer cells may acquire the capacity for autonomous and dysregulated proliferation through the uncontrolled production of specific molecules that promote cell growth (growth factors) or through abnormal, enhanced expression of specific proteins (growth factor receptors) on the cell membranes to which growth factors selectively bind. Both processes trigger a series of intracellular signals that ultimately lead to the proliferation of cancer cells, induction of angiogenesis, and metastasis. 1 The majority of human epithelial cancers are marked by functional activation of growth factors and receptors of the epidermal growth factor receptor (EGFR) family. Given this phenomenon, EGFR was the first growth factor receptor to be proposed as a target for cancer therapy. After 20 years of drug development, four EGFR antagonists are currently available for the treatment of four metastatic epithelial cancers: non-small-cell lung cancer, squamous-cell carcinoma of the head and neck, colorectal cancer, and pancreatic cancer. Less information is available about the use of EGFR antagonists in the treatment of earlier stages of cancer. This article summarizes the mechanisms of action of EGFR inhibitors, presents the clinical evidence of their anticancer activity, and considers the current, and controversial, clinical issues with respect to their optimal use in the treatment of patients with cancer.EGFR in Hum a n C a rcinogenesis EGFR is a transmembrane receptor belonging to a family of four related proteins (Fig. 1). 2 Ten different ligands can selectively bind to each receptor. After a ligand binds to a single-chain EGFR, the receptor forms a dimer 3 that signals within the cell by activating receptor autophosphorylation through tyrosine kinase activity. 3 Autophosphorylation triggers a series of intracellular pathways that may result in cancer-cell proliferation, blocking apoptosis, activating invasion and metastasis, and stimulating tumor-induced neovascularization. 3,4 Dev el opment of EGFR A ntag onis t s for A ntic a ncer Ther a pyThe first anti-EGFR drugs were developed in the 1980s. 18 Two classes of EGFR antagonists have been successfully tested in phase 3 trials and are now in clinical use: anti-EGFR monoclonal antibodies and small-molecule EGFR tyrosine kinase inhibitors (Tables 1 and 2). 4,5,[10][11][12]18 Anti-EGFR monoclonal antibodies, such as cetuximab, bind to the extracellular domain of EGFR when it is in the inactive configuration, compete for receptor binding by occluding the ligand-binding region, and thereby block ligand-induced EGFR tyrosine kinase activation. 4,5,19 Small-molecule EGFR tyrosine kinase inhibitors, such as erlotinib and gefitinib, compete reversibly with ATP to bind to the intracellular catalytic domain of EGFR tyrosine kinase and, thus, inhibit EGFR autophosphorylation and downstream signaling. Anti-EGFR monoclonal antibodies recognize EGFR The New England Journal of Medicine Downloaded from nejm.org at DUKE MEDICAL CENTER LIBRARY on September 28, 2012. For personal use only. No ot...

Molecular pathology of lung cancer: key to personalized medicine

“…5,6,14,63,64 In adenocarcinomas, the majority of mutations have been identified in exons 18-21 of the EGFR gene. 9,65,66 These mutations can be roughly classified into three major categories: in-frame deletions in exon 19, insertion mutations in exon 20, and missense mutations in exons 18-21 ( Figure 2).…”

“…[10][11][12][13] EGFR and members of its family have an important role in carcinogenesis through their involvement in the modulation of cell proliferation, apoptosis, cell motility, and neovascularization. [12][13][14][15][16] EGFR alterations have been implicated in the pathogenesis and progression of many malignancies. 13,[17][18][19][20][21] The incidence of EGFR mutations in unselected tumors with non-small cell histology ranges from 10 to 50%, depending upon the ethnic makeup of the patient population and the detection methods used for mutation analysis; 95% of such mutations have been found in adenocarcinomas.…”

Everolimus restores gefitinib sensitivity in resistant non-small cell lung cancer cell lines

“…A higher probability of response appears to be associated with certain biological and clinical characteristics (such as adenocarcinoma histotype, female sex, never smoking status and Asian ethnic origin) and with biological features of the tumor [5].…”

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“…As target for our PD-L1-blocking bsAb we selected the epidermal growth factor receptor (EGFR), a well-established oncogenic tumor-associated surface antigen that is overexpressed and/or mutated in various epithelial malignancies, including colorectal cancer and non-small-cell lung cancer. 15 , 16 Of note, FDA-approved anti-EGFR antibodies necitumumab and cetuximab 17 inhibit oncogenic EGFR signaling and show clinical efficacy in cancers also responsive to PD-1/PD-L1 checkpoint inhibition. 18 …”