Mechanisms of Resistance to Epidermal Growth Factor Receptor (EGFR) in Non-Small Cell Lung Cancer

A change in the treatment paradigm for nonsmall cell lung cancer followed the discovery of activating epidermal growth factor receptor (EGFR) mutations in patients who responded to treatment with EGFR tyrosine kinase inhibitors (EGFR TKIs) such as gefitinib or erlotinib. However, nonsmall cell lung cancer patients with activating EGFR mutations eventually develop resistance to reversible EGFR TKIs, which may be the result of secondary acquired EGFR mutations or other mechanisms indirectly related to the EGFR genotype. In addition, up to 10% of EGFR-mutated tumors exhibit primary resistance to first-generation EGFR TKIs. Typically, this resistance is caused by insertion mutations in exon 20 or by other somatic mutations in genes that have an impact on the EGFR signaling pathway, such as KRAS, BRAF, PI3KCA and PTEN loss. Several ongoing clinical trials with novel targeted therapies are aimed at overcoming resistance to first-generation EGFR TKIs. This chapter will describe the known mechanisms of primary and acquired EGFR TKI resistance in patients with nonsmall cell lung cancer.