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. Scheel, Svenja 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 () and Martin L. Sos ()
Additional contact information
Jana Fassunke: University Hospital of Cologne
Fabienne Müller: University Hospital of Cologne
Marina Keul: TU Dortmund University
Sebastian Michels: University Hospital Cologne
Marcel A. Dammert: University Hospital of Cologne
Anna Schmitt: University of Cologne
Dennis Plenker: University Hospital of Cologne
Jonas Lategahn: TU Dortmund University
Carina Heydt: University Hospital of Cologne
Johannes Brägelmann: University Hospital of Cologne
Hannah L. Tumbrink: University Hospital of Cologne
Yannic Alber: TU Dortmund University
Sebastian Klein: University Hospital of Cologne
Alena Heimsoeth: University Hospital of Cologne
Ilona Dahmen: University of Cologne
Rieke N. Fischer: University Hospital Cologne
Matthias Scheffler: University Hospital Cologne
Michaela A. Ihle: University Hospital of Cologne
Vanessa Priesner: University Hospital Cologne
Andreas H. Scheel: University Hospital of Cologne
Svenja Wagener: University Hospital of Cologne
Anna Kron: University Hospital Cologne
Konrad Frank: University Hospital of Cologne
Katia Garbert: University Hospital of Cologne
Thorsten Persigehl: University Hospital of Cologne
Michael Püsken: University Hospital of Cologne
Stefan Haneder: University Hospital of Cologne
Bernhard Schaaf: Hospital Dortmund gGmbH
Ernst Rodermann: Onkologie Rhein-Sieg
Walburga Engel-Riedel: Lung Hospital Cologne Merheim, City of Cologne Municipal Hospitals
Enriqueta Felip: Vall d’Hebron University Hospital
Egbert F. Smit: Netherlands Cancer Institute
Sabine Merkelbach-Bruse: University Hospital of Cologne
H. Christian Reinhardt: University of Cologne
Stefan M. Kast: TU Dortmund University
Jürgen Wolf: University Hospital Cologne
Daniel Rauh: TU Dortmund University
Reinhard Büttner: University Hospital of Cologne
Martin L. Sos: University Hospital of Cologne

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-018-07078-0 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-07078-0

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-018-07078-0

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().