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Fassunke, Jana; Müller, Fabienne; Keul, Marina; Michels, Sebastian; Dammert, Marcel A.; Schmitt, Anna; Plenker, Dennis; Lategahn, Jonas; Heydt, Carina; Brägelmann, Johannes; Tumbrink, Hannah L.; Alber, Yannic; Klein, Sebastian; Heimsoeth, Alena; Dahmen, Ilona; Fischer, Rieke N.; Scheffler, Matthias; Ihle, Michaela A.; Priesner, Vanessa; Scheel, Andreas H.; Wagener, Svenja; Kron, Anna; Frank, Konrad; Garbert, Katia; [...]

Overcoming EGFRG724S-mediated osimertinib resistance through unique binding characteristics of second-generation EGFR inhibitors

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  • Medientyp: E-Artikel
  • Titel: Overcoming EGFRG724S-mediated osimertinib resistance through unique binding characteristics of second-generation EGFR inhibitors
  • Beteiligte: Fassunke, Jana; Müller, Fabienne; Keul, Marina; Michels, Sebastian; Dammert, Marcel A.; Schmitt, Anna; Plenker, Dennis; Lategahn, Jonas; Heydt, Carina; Brägelmann, Johannes; Tumbrink, Hannah L.; Alber, Yannic; Klein, Sebastian; Heimsoeth, Alena; Dahmen, Ilona; Fischer, Rieke N.; Scheffler, Matthias; Ihle, Michaela A.; Priesner, Vanessa; Scheel, Andreas H.; Wagener, Svenja; Kron, Anna; Frank, Konrad; Garbert, Katia; [...]
  • Erschienen: Springer Science and Business Media LLC, 2018
  • Erschienen in: Nature Communications
  • Sprache: Englisch
  • DOI: 10.1038/s41467-018-07078-0
  • ISSN: 2041-1723
  • Schlagwörter: General Physics and Astronomy ; General Biochemistry, Genetics and Molecular Biology ; General Chemistry ; Multidisciplinary
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:title>Abstract</jats:title><jats:p>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 <jats:italic>EGFR</jats:italic><jats:sup>T790M</jats:sup>-negative but <jats:italic>EGFR</jats:italic><jats:sup>G724S</jats:sup>-positive subclones and osimertinib resistance. We demonstrate that <jats:italic>EGFR</jats:italic><jats:sup>G724S</jats:sup> limits the activity of third-generation EGFR inhibitors both in vitro and in vivo. Structural analyses and computational modeling indicate that <jats:italic>EGFR</jats:italic><jats:sup>G724S</jats:sup> 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 <jats:italic>EGFR</jats:italic><jats:sup>G724S</jats:sup>-mediated resistance. In the case of afatinib this profile translates into a robust reduction of colony formation and tumor growth of <jats:italic>EGFR</jats:italic><jats:sup>G724S</jats:sup>-driven cells. Our data provide a mechanistic basis for the osimertinib-induced selection of <jats:italic>EGFR</jats:italic><jats:sup>G724S</jats:sup>-mutant clones and a rationale to treat these patients with clinically approved second-generation EGFR inhibitors.</jats:p>
  • Zugangsstatus: Freier Zugang