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Updated: Feb 2, 2026
Identification of EGFR and RAS Inhibitors using Caenorhabditis elegans
Published on: October 5, 2020
Overcoming EGFRG724S-mediated osimertinib resistance through unique binding characteristics of second-generation EGFR
Jana Fassunke1, Fabienne Müller2,3, Marina Keul4
1Institute of Pathology, University Hospital of Cologne, Kerpener Str. 62, 50937, Cologne, Germany.
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.
Insights
Acquired resistance to osimertinib in lung adenocarcinoma can be driven by EGFR G724S mutations. Second-generation EGFR inhibitors, like afatinib, effectively overcome this resistance by maintaining kinase activity against these resistant clones.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Acquired resistance to targeted therapies is a significant clinical problem in lung adenocarcinoma.
- Identifying resistance mechanisms is crucial for developing effective treatment strategies.
Purpose of the Study:
- To investigate the mechanism of osimertinib resistance in lung adenocarcinoma.
- To identify alternative therapeutic strategies for patients with specific resistance mutations.
Main Methods:
- Genomic analysis to identify EGFR mutations in resistant tumors.
- In vitro and in vivo experiments to assess the activity of EGFR inhibitors.
- Structural and computational modeling to understand drug-target interactions.
- Kinetic profiling and inhibitor screening.
Main Results:
- EGFR G724S mutations were associated with osimertinib resistance in a subset of lung adenocarcinoma patients.
- EGFR G724S limits the efficacy of third-generation EGFR inhibitors by altering kinase conformation.
- Second-generation EGFR inhibitors, including afatinib, retain activity against EGFR G724S mutations.
- Afatinib demonstrated significant reduction in tumor growth and colony formation in EGFR G724S-driven models.
Conclusions:
- EGFR G724S mutations provide a mechanistic basis for osimertinib resistance.
- Clinically approved second-generation EGFR inhibitors represent a viable treatment option for patients with EGFR G724S-mediated resistance.
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