Clinical Colorectal Cancer Supplement April 2005 • S19 Introduction In 2005, 145,290 new cases of and 56,290 deaths from col- orectal cancer (CRC) are expected to occur in the United States. 1 The current chemotherapeutic options for patients with metastatic CRC are capecitabine, 5-fluorouracil (5-FU), irinotecan, and oxaliplatin. 2-4 Although these traditional chemotherapeutic options have improved the median overall survival from 12 to 18-21 months, limitations with this treat- ment remain. 5 Therefore, oncologists are currently investigat- ing several novel targeted agents as single agents and in com- bination with chemotherapy to assess the potential for in- creased efficacy. Preclinical and clinical studies have shown that targeting the epidermal growth factor receptor (EGFR) is a valid strategy for cancer therapy. 6 The goal of this review is to provide an update of the most recent data of anti-EGFR therapy in metastatic CRC. Epidermal Growth Factor Structure and Function The EGFR, a 170-kd transmembrane glycoprotein, is a member of the type I receptor tyrosine kinase (TK) family. Three domains of EGFR can be distinguished: the ligand- binding extracellular domain, a lipophilic transmembrane do- main, and a signal-transducing TK domain located intracellu- lary. 7-9 The most important natural ligands of EGFR, ie, epi- dermal growth factor and transforming growth factor–α, in- duce a receptor dimerization, followed by internalization of the receptor/ligand complex that subsequently leads to the ac- tivation of the TK signal transduction. 7,8 Expression of EGFR has been correlated with various different cellular processes involved in carcinogenesis such as cell proliferation, inhibition of apoptosis, angiogenesis, cell motility, and metastasis. 7,9 Preclinical studies have shown that anti-EGFR agents are able Epidermal Growth Factor Receptor as a Target for Chemotherapy Abstract Submitted: Jan 3, 2005; Revised: Mar 22, 2005; Accepted: Mar 28, 2005 Address for correspondence: Heinz-Josef Lenz, MD, Colorectal Center, USC/Norris Comprehensive Cancer Center, Keck School of Medicine, 1441 Eastlake Ave, Suite 3456, Los Angeles, CA 90033 Fax: 323-865-0061; e-mail: lenz@usc.edu Division of Medical Oncology, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles Daniel Vallböhmer, Heinz-Josef Lenz The epidermal growth factor receptor (EGFR) is overexpressed in as many as 77% of colorectal cancer (CRC) cases.The EGFR is known to be involved in carcinogenetic processes such as cell proliferation, apoptosis, angio- genesis, cell motility, and metastasis. Preclinical and clinical studies have shown that targeting EGFR is a valid strate- gy for anticancer therapy. Currently, 2 classes of anti-EGFR agents are in phase II/III clinical development: monoclonal antibodies and tyrosine kinase (TK) inhibitors. The most established monoclonal antibody is cetuximab, the only EGFR inhibitor that is currently approved for use in patients with metastatic CRC. Several clinical studies of cetux- imab, as a single agent or in combination with irinotecan, have shown promising efficacy in patients with metastatic CRC.Two other monoclonal antibodies, matuzumab (EMD 72000) and panitumumab (ABG-EGF), also have shown activity against EGFR-expressing CRC but are still in the early stage of clinical development.The activity of the EGFR TK inhibitors erlotinib and gefitinib have already been investigated in clinical phase III trials in patients with non–small-lung cancer, suggesting that sequential rather than concurrent erlotinib/gefitinib–based treatment pro- vides a benefit in clinical outcome.The EGFR-targeting agents are reasonably well tolerated and have limited over- lapping toxicities in combination with other cytotoxic drugs.The most common side effect of anti-EGFR treatment is an acneiform skin rash, which is associated with the clinical outcome of treatment with monoclonal antibodies and TK inhibitors. Future clinical studies are needed to establish these EGFR-targeting agents in anticancer treat- ment to investigate efficacy of therapies combining EGFR-targeted agents with other targeting agents and to de- scribe additional markers determining the clinical outcome of anti-EGFR therapy. Clinical Colorectal Cancer, Vol. 5, Suppl. 1, S19-S27, 2005 Key words: Cetuximab, Erlotinib, Gefitinib, Matuzumab, Monoclonal antibodies, Panitumumab, Tyrosine kinase inhibitors Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Cancer Information Group, ISSN #1533-0028, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.