Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Oncol. Oct 10, 2016; 7(5): 340-351
Published online Oct 10, 2016. doi: 10.5306/wjco.v7.i5.340
Oncogenic fingerprint of epidermal growth factor receptor pathway and emerging epidermal growth factor receptor blockade resistance in colorectal cancer
Zain A Sobani, Ashwin Sawant, Mikram Jafri, Amit Keith Correa, Ibrahim Halil Sahin
Zain A Sobani, Department of Medicine, Maimonides Medical Center, New York, NY 11219, United States
Ashwin Sawant, Amit Keith Correa, Ibrahim Halil Sahin, Department of Medicine, Icahn School of Medicine at Mount Sinai St Luke’s Roosevelt Hospital Center, New York, NY 10019, United States
Mikram Jafri, Department of Medicine, Albany Stratton Veterans Hospital, Albany, New York, NY 12208, United States
Author contributions: All authors contributed to this manuscript.
Conflict-of-interest statement: All authors have no financial or non-financial conflict of interest including but not limited to commercial, personal, political, intellectual, or religious interests related to this manuscript.
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: Ibrahim Halil Sahin, MD, Department of Medicine, Icahn School of Medicine at Mount Sinai St Luke’s Roosevelt Hospital Center, 1000 10th Avenue, New York, NY 10019, United States.
Telephone: +1-212-5234000
Received: April 25, 2016
Peer-review started: April 26, 2016
First decision: June 16, 2016
Revised: July 18, 2016
Accepted: August 6, 2016
Article in press: August 8, 2016
Published online: October 10, 2016

Epidermal growth factor receptor (EGFR) has been an attractive target for treatment of epithelial cancers, including colorectal cancer (CRC). Evidence from clinical trials indicates that cetuximab and panitumumab (anti-EGFR monoclonal antibodies) have clinical activity in patients with metastatic CRC. The discovery of intrinsic EGFR blockade resistance in Kirsten RAS (KRAS)-mutant patients led to the restriction of anti-EGFR antibodies to KRAS wild-type patients by Food and Drug Administration and European Medicine Agency. Studies have since focused on the evaluation of biomarkers to identify appropriate patient populations that may benefit from EGFR blockade. Accumulating evidence suggests that patients with mutations in EGFR downstream signaling pathways including KRAS, BRAF, PIK3CA and PTEN could be intrinsically resistant to EGFR blockade. Recent whole genome studies also suggest that dynamic alterations in signaling pathways downstream of EGFR leads to distinct oncogenic signatures and subclones which might have some impact on emerging resistance in KRAS wild-type patients. While anti-EGFR monoclonal antibodies have a clear potential in the management of a subset of patients with metastatic CRC, further studies are warranted to uncover exact mechanisms related to acquired resistance to EGFR blockade.

Keywords: Epidermal growth factor receptor, Oncogenic signature, Kirsten RAS, BRAF, Cetuximab, Panitumumab, Epidermal growth factor receptor blockade resistance

Core tip: Epidermal growth factor receptor (EGFR) blockade treatment is a well-established targeted therapy in metastatic colorectal cancer (CRC) patients. However, a limited number of patients benefit from EGFR inhibition, with limited time duration of response. This review article discusses the most recent updates from the current-state-of-the-science related to molecular pathways of EGFR signaling, the mechanism of action and efficacy of EGFR blockade treatment, and possible molecular pathways related to EGFR blockade resistance in CRC. We further discuss potential mechanisms contributing to targeted EGFR inhibition. Lastly, future perspectives are discussed to shed some light on efforts to overcome this potential challenge in the era of targeted treatment.