Mechanisms of resistance to EGFR inhibitors

The epidermal growth factor receptor ( EGFR) autocrine pathway plays a crucial role in human cancer, contributing to a number of highly relevant processes in tumor development and progression, including cell proliferation, regulation of apoptotic cell death, angiogenesis, and metastatic spread. For these reasons, the EGFR is one of the most studied and exploited targets for molecular cancer therapy. Two classes of anti-EGFR agents have entered clinical practice: monoclonal antibodies and small molecules targeting the receptor tyrosine kinase. They have shown activity alone and in combination with conventional antitumor treatments, such as chemotherapy or radiation therapy. However, preclinical and clinical studies have demonstrated the occurrence of spontaneous or acquired resistance to these drugs. Since EGFR is implicated in a wide array of intracellular functions, the phenomenon of resistance to its inhibitors may result from the derangement of different molecular pathways, including autocrine/paracrine production of ligands, receptor mutations, constitutive activation of downstream signaling proteins, and activation of alternative pathways. This review presents the experimental evidence underlying the main mechanisms of resistance to EGFR inhibitors.