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

• DOI: 10.1038/s41467-018-07078-0
• Publication Date: 2018-11-01T12:16:57Z
• Authors: 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. Scheel; Svenja Wagener; Anna Kron; Konrad Frank; Katia Garbert; Thorsten Persigehl; Michael Püsken; Stefan Haneder; Bernhard Schaaf; Ernst Rodermann; Walburga Engel-Ri...; Enriqueta Felip; Egbert F. Smit; Sabine Merkelbach...; H. Christian Rein...; Stefan M. Kast; Jürgen Wolf; Daniel Rauh; Reinhard Büttner; Martin L. Sos
• Keywords: Osimertinib; Afatinib; EGFR Inhibitors

Abstract The emergence of acquired resistance against targeted drugs remains a major clinical challenge in lung adenocarcinoma patients. In subgroup these patients we identified an association between selection EGFR T790M -negative but G724S -positive subclones and osimertinib resistance. We demonstrate that limits the activity third-generation inhibitors both vitro vivo. Structural analyses computational modeling indicate mutations may induce conformation glycine-rich loop, which is incompatible with binding TKIs. Systematic inhibitor screening in-depth kinetic profiling validate findings show second-generation retain kinase affinity overcome -mediated case afatinib this profile translates into robust reduction colony formation tumor growth -driven cells. Our data provide mechanistic basis for osimertinib-induced -mutant clones rationale to treat clinically approved inhibitors.