T790M: revealing the secrets of a gatekeeper.

Non-small-cell lung cancers that harbor activating mutations in the 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 has limited the long-term efficacy of these targeted therapies. This "gatekeeper" T790M alteration remains the only validated and relevant second-site resistance mutation for , allowing for focused research to understand and overcome T790M-mediated resistance. The current review focuses on T790M by discussing mechanisms of resistance mediated by T790M, reviewing development of novel third-generation EGFR TKIs targeting T790M, and highlighting current research on overcoming resistance to third-generation T790M TKIs.