Topic Highlight
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jul 28, 2016; 22(28): 6345-6361
Published online Jul 28, 2016. doi: 10.3748/wjg.v22.i28.6345
Mechanisms of resistance to anti-epidermal growth factor receptor inhibitors in metastatic colorectal cancer
Vincenzo Sforza, Erika Martinelli, Fortunato Ciardiello, Valentina Gambardella, Stefania Napolitano, Giulia Martini, Carminia della Corte, Claudia Cardone, Marianna L Ferrara, Alfonso Reginelli, Giuseppina Liguori, Giulio Belli, Teresa Troiani
Vincenzo Sforza, Erika Martinelli, Fortunato Ciardiello, Stefania Napolitano, Giulia Martini, Carminia della Corte, Claudia Cardone, Marianna L Ferrara, Teresa Troiani, Oncologia medica, Dipartimento di Medicina Clinica e Sperimentale “F. Magrassi e A. Lanzara”, Seconda Università degli Studi di Napoli, 80131 Naples, Italy
Valentina Gambardella, Department of Medical Oncology, Biomedical Research Institute INCLIVA, University of Valencia, 46940 Valencia, Spain
Alfonso Reginelli, Department of Internal and Experimental Medicine, Magrassi-Lanzara, Institute of Radiology, Seconda Università di Napoli, 80131 Naples, Italy
Giuseppina Liguori, Department of Pathology, Istituto Nazionale Tumori “Fond. Pascale” - IRCCS, 80142 Napoli, Italy
Giulio Belli, Department of General and Hepato-Pancreato-Biliary Surgery, S. M. Loreto Nuovo Hospital, 80131 Naples, Italy
Author contributions: Sforza V performed research and wrote the paper; Martinelli E , Ciardiello F, Gambardella V, Napolitano S, Martini G, della Corte C, Cardone C, Ferrara ML, Reginelli A, Liguori G, Belli G and Troiani T contributed critical revision of the manuscript for important intellectual content.
Conflict-of-interest statement: No conflict of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Vincenzo Sforza, MD, Oncologia medica, Dipartimento di Medicina Clinica e Sperimentale “F. Magrassi e A. Lanzara”, Seconda Università degli Studi di Napoli, via S. Pansini 5, 80131 Naples, Italy.
Telephone: +39-81-5666729 Fax: +39-81-5666745
Received: March 29, 2016
Peer-review started: April 4, 2016
First decision: May 12, 2016
Revised: June 11, 2016
Accepted: July 6, 2016
Article in press: July 6, 2016
Published online: July 28, 2016

The prognosis of patients with metastatic colorectal cancer (mCRC) remain poor despite the impressive improvement of treatments observed over the last 20 years that led to an increase in median overall survival from 6 mo, with the only best supportive care, to approximately 30 mo with the introduction of active chemotherapy drugs and targeted agents. The monoclonal antibodies (moAbs) cetuximab and panitumumab, directed against the epidermal growth factor receptor (EGFR), undoubtedly represent a major step forward in the treatment of mCRC, given the relevant efficacy in terms of progression-free survival, overall survival, response rate, and quality of life observed in several phase III clinical trials among different lines of treatment. However, the anti-EGFR moAbs were shown only to be effective in a subset of patients. For instance, KRAS and NRAS mutations have been identified as biomarkers of resistance to these drugs, improving the selection of patients who might derive a benefit from these treatments. Nevertheless, several other alterations might affect the response to these drugs, and unfortunately, even the responders eventually become resistant by developing secondary (or acquired) resistance in approximately 13-18 mo. Several studies highlighted that the landscape of responsible alterations of both primary and acquired resistance to anti-EGFR drugs biochemically converge into MEK-ERK and PIK3CA-AKT pathways. In this review, we describe the currently known mechanisms of primary and acquired resistance to anti-EGFR moAbs together with the various strategies evaluated to prevent, overcame or revert them.

Keywords: Metastatic colorectal cancer, Epidermal growth factor receptor, Resistance, Mutation, KRAS, NRAS, BRAF, PIK3CA, MET, Monoclonal antibodies

Core tip: The treatment with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies cetuximab and panitumumab in metastatic colorectal cancer is unfortunately burdened by the lack of clinical and molecular biomarkers that correlate with treatment response. Primary and acquired resistance have been shown to be the major culprits of the failure of anti-EGFR treatments. However, a deeper understanding of the molecular basis underlying both types of resistance has led to the proposal of several approaches designed to prevent, overcome or revert the drug resistance. Nevertheless, these approaches deserve further clinical investigation to allow us to use EGFR-targeted therapies more effectively in the correct population.