SAGE-Hindawi Access to Research Pathology Research International Volume 2011, Article ID 219309, 11 pages doi:10.4061/2011/219309 Review Article Impact of KRAS Mutations on Management of Colorectal Carcinoma Kevin M. Sullivan and Peter S. Kozuch Department of Medicine, Section of Hematology/Oncology, Albert Einstein College of Medicine, Beth Israel Medical Center, Phillips Ambulatory Care Center, 10 Union Square East, Suite 4C, NY 10003, USA Correspondence should be addressed to Peter S. Kozuch, pkozuch@chpnet.org Received 28 September 2010; Revised 2 January 2011; Accepted 10 January 2011 Academic Editor: Wade Samowitz Copyright © 2011 K. M. Sullivan and P. S. Kozuch. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The epidermal growth factor receptor (EGFR) pathway is a therapeutic target in the management of colorectal cancer (CRC). EGFR antagonists are active in this disease; however, only a subset of patients respond to such therapy. A Kirsten ras sarcoma viral oncogene (KRAS) wild-type (WT) status of the tumor is necessary, but possibly not suﬃcient, for a response to anti-EGFR monoclonal antibody therapy. Mechanisms of primary resistance to such therapy in patients harboring KRAS WT tumors are discussed. Strategies to overcome resistance to anti-EGFR monoclonal antibody therapy, including novel agents and combinations of novel therapies, are explored. Also, the use of anti-EGFR monoclonal antibodies in the adjuvant and neoadjuvant setting is reviewed. 1. Introduction Tumor growth and progression depends in part on the activity of cell surface membrane receptors which control signal transduction pathways. These growth factor receptors can have aberrations in their expression and regulation and activation of growth factor pathways is common in many malignancies [1]. The EGFR, a transmembrane glycoprotein also called ERBB-1 or HER1, is a member of a family of receptor tyrosine kinases (TKs). The EGFR is involved in signaling pathways controlling cell growth, diﬀerentiation, and proliferation and is expressed in many diﬀerent types of normal tissues as well as several tumor types, including CRC [2, 3]. Figure 1 illustrates the main EGFR signaling pathways described [4]. When a ligand binds to the EGFR, the receptor forms a dimer resulting in a signaling cascade within the cell via tyrosine kinase activity [5]. This signaling cascade occurs by the activation of receptor autophospho- rylation which triggers a number of intracellular pathways regulating cell proliferation, prevention of apoptosis, and promotion of invasion, metastasis, and neovascularization [6]. The proto-oncogene c-erb-B encodes the EGFR, and activation of the proto-oncogene results in EGFR expression in many tumors [7, 8]. There was therefore interest in investigating this pathway as a potential anticancer therapy target. Pharmacologically, there are two classes of EGFR antag- onists currently in clinical use: antiEGFR monoclonal anti- bodies directed against the extracellular domain of the recep- tor and oral small-molecule EGFR TK inhibitors which block the receptor TK activity competitively [10]. The antiEGFR monoclonal antibodies, cetuximab and panitumumab, act by binding to the extracellular region of the EGFR and therefore block the ligand-binding region which prevents ligand- induced TK activation [11]. These monoclonal antibodies solely recognize the EGFR, making them very selective for their target [5]. The small-molecule EGFR TK inhibitors, erlotinib and geﬁtinib, inhibit the catalytic activity of the TK by competing with adenosine triphosphate (ATP) to bind to the intracellular domain [10]. These small-molecule inhibitors are not exclusive to the EGFR pathway and can block diﬀerent receptor tyrosine kinases, such as the vascular endothelial growth factor (VEGF) receptor and other members of the EGFR family.