Overcoming EGFRG724S-mediated osimertinib resistance through unique binding characteristics of second-generation EGFR inhibitors
J. Fassunke, F. Müller, M. Keul, S. Michels, M.A. Dammert, A. Schmitt, D. Plenker, J. Lategahn, C. Heydt, J. Brägelmann, H.L. Tumbrink, Y. Alber, S. Klein, A. Heimsoeth, I. Dahmen, R.N. Fischer, M. Scheffler, M.A. Ihle, V. Priesner, A.H. Scheel, S. Wagener, A. Kron, K. Frank, K. Garbert, T. Persigehl, M. Püsken, S. Haneder, B. Schaaf, E. Rodermann, W. Engel-Riedel, E. Felip, E.F. Smit, S. Merkelbach-Bruse, H. C. Reinhardt, S.M. Kast, J. Wolf, D. Rauh, R. Büttner, M. Sos
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.