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Nat Commun ; 9(1): 4655, 2018 11 07.
Article in English | MEDLINE | ID: mdl-30405134

ABSTRACT

The emergence of acquired resistance against targeted drugs remains a major clinical challenge in lung adenocarcinoma patients. In a subgroup of these patients we identified an association between selection of EGFRT790M-negative but EGFRG724S-positive subclones and osimertinib resistance. We demonstrate that EGFRG724S limits the activity of third-generation EGFR inhibitors both in vitro and in vivo. Structural analyses and computational modeling indicate that EGFRG724S mutations may induce a conformation of the glycine-rich loop, which is incompatible with the binding of third-generation TKIs. Systematic inhibitor screening and in-depth kinetic profiling validate these findings and show that second-generation EGFR inhibitors retain kinase affinity and overcome EGFRG724S-mediated resistance. In the case of afatinib this profile translates into a robust reduction of colony formation and tumor growth of EGFRG724S-driven cells. Our data provide a mechanistic basis for the osimertinib-induced selection of EGFRG724S-mutant clones and a rationale to treat these patients with clinically approved second-generation EGFR inhibitors.


Subject(s)
Drug Resistance, Neoplasm/drug effects , ErbB Receptors/antagonists & inhibitors , Piperazines/pharmacology , Protein Kinase Inhibitors/pharmacology , Acrylamides , Aniline Compounds , Animals , Cell Line, Tumor , Disease Progression , ErbB Receptors/chemistry , ErbB Receptors/metabolism , Female , Humans , Kinetics , Mice , Mice, Nude , Mutation/genetics , NIH 3T3 Cells , Piperazines/chemistry , Protein Binding/drug effects , Protein Conformation , Protein Kinase Inhibitors/chemistry
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