Role and mechanisms of resistance of epidermal growth factor receptor antagonists in the treatment of colorectal cancer

Although epidermal growth factor receptor (EGFR) inhibitors have progressively become a relevant therapeutic arm in the treatment of patients with advanced colorectal cancer, the responses achieved are not durable and resistance invariably occurs. The advances in sequencing technology have allowed not only a more profound molecular tumor characterization but also the identification of the different molecular pathways involved in drug resistance and disease progression. These biological improvements have encouraged researchers to design clinical studies testing novel target therapies. AREAS COVERED: After discussing the results of key Phase III randomized trials and providing commentary on the most promising novel agents (Sym004, MM-151, GA201 and MEHD7945A), the authors present the future steps ahead toward a real tailored treatment. EXPERT OPINION: EGFR inhibitors are highly effective in the advanced disease setting. Although the negative predictive role of RAS and possibly BRAF mutations has already been established, more comprehensive efforts are needed to optimize the use of these drugs. At the same time, understanding the underlying biology will help basic scientists to develop new compounds able to overcome both primary and acquired resistance and help clinical researchers to test novel drugs within adequately designed trials whose results eventually are expected to reshape the overall treatment strategy.