Lung Cancer: Targets and Therapy (Oct 2017)
EGFR T790M: revealing the secrets of a gatekeeper
Abstract
Brian Ko, Daniel Paucar, Balazs Halmos Department of Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, New York, NY, USA Abstract: Non-small-cell lung cancers that harbor activating mutations in the EGFR gene represent an important molecularly defined subset of lung cancer. Despite dramatic initial responses with first- and second-generation EGFR-directed tyrosine-kinase inhibitors (TKIs) against these cancers, the development of a dominant and frequent resistance mechanism through a threonine–methionine amino acid substitution at position 790 (T790M) of EGFR has limited the long-term efficacy of these targeted therapies. This “gatekeeper” EGFR T790M alteration remains the only validated and relevant second-site resistance mutation for EGFR, allowing for focused research to understand and overcome EGFR T790M-mediated resistance. The current review focuses on EGFR T790M by discussing mechanisms of resistance mediated by EGFR T790M, reviewing development of novel third-generation EGFR TKIs targeting EGFR T790M, and highlighting current research on overcoming resistance to third-generation EGFR T790M TKIs. Keywords: lung cancer, epidermal growth factor receptor, T790M, targeted therapy, resistance
