Oncogenic Activity of Epidermal Growth Factor Receptor Kinase Mutant Alleles Is Enhanced by the T790M Drug Resistance Mutation

摘要: Activating mutations in the epidermal growth factor receptor (EGFR) characterize a subset of non-small cell lung cancers (NSCLC) with extraordinary sensitivity to targeted tyrosine kinase inhibitors (TKI). A single secondary EGFR mutation, T790M, arising cis primary activating confers acquired resistance these drugs. However, T790M mutation is also detected absence drug selection, suggesting that it may provide advantage. We show here although alone has only modest effect on function, when combined characteristic L858R or del746-750, results dramatic enhancement activity. The double mutants potent ligand-independent autophosphorylation associated altered cellular phenotypes, soft agar colony formation, and tumorigenesis nude mice. significant gain-of-function properties explain their initial presence before selection rapid as during therapy gefitinib/erlotinib, suggests they contribute adverse clinical course TKI-resistant NSCLC.