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

Jana Fassunke, Fabienne Müller, Marina Keul, Sebastian Michels, Marcel A Dammert, Anna Schmitt, Dennis Plenker, Jonas Lategahn, Carina Heydt, Johannes Brägelmann, Hannah L Tumbrink, Yannic Alber, Sebastian Klein, Alena Heimsoeth, Ilona Dahmen, Rieke N Fischer, Matthias Scheffler, Michaela A Ihle, Vanessa Priesner, Andreas H ScheelSvenja Wagener, Anna Kron, Konrad Frank, Katia Garbert, Thorsten Persigehl, Michael Püsken, Stefan Haneder, Bernhard Schaaf, Ernst Rodermann, Walburga Engel-Riedel, Enriqueta Felip, Egbert F Smit, Sabine Merkelbach-Bruse, H Christian Reinhardt, Stefan M Kast, Jürgen Wolf, Daniel Rauh, Reinhard Büttner, Martin L Sos

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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.

Original languageEnglish
Pages (from-to)4655
JournalNature Communications
Issue number1
Publication statusPublished - 7 Nov 2018

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