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Updated: Feb 18, 2026
Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
Published on: August 11, 2017
Recent Progress of Small-Molecule Epidermal Growth Factor Receptor (EGFR) Inhibitors against C797S Resistance in
Lingfeng Chen1,2, Weitao Fu1, Lulu Zheng1
1Chemical Biology Research Center at School of Pharmaceutical Sciences , Wenzhou Medical University , Wenzhou , Zhejiang 325035 , China.
Abstract:
The epidermal growth factor receptor (EGFR) has been a particular interest for drug development for treatment of non-small-cell lung cancer (NSCLC). The current third-generation EGFR small-molecule inhibitors, especially osimertinib, are at the forefront clinically for treatment of patients with NSCLC. However, a high percentage of these treated patients developed a tertiary cystein-797 to serine-790 (C797S) mutation in the EGFR kinase domain. This C797S mutation is thought to induce resistance to all current irreversible EGFR TKIs. In this Miniperspective, we present key mechanisms of resistance in response to third-generation EGFR TKIs, and emerging reports on novel EGFR TKIs to combat the resistance. Specifically, we analyze the allosteric and ATP-competitive inhibitors in terms of drug discovery, binding mechanism, and their potency and selectivity against EGFR harboring C797S mutations. Lastly, we provide some perspectives on new challenges and future directions in this field.
Insights
Third-generation EGFR inhibitors are effective for non-small-cell lung cancer (NSCLC), but resistance emerges due to the C797S mutation. Novel inhibitors targeting this mutation show promise for overcoming treatment resistance.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Epidermal growth factor receptor (EGFR) is a key target in non-small-cell lung cancer (NSCLC) drug development.
- Third-generation EGFR inhibitors like osimertinib are clinically significant but face resistance.
- The C797S mutation in EGFR confers resistance to current irreversible EGFR tyrosine kinase inhibitors (TKIs).
Purpose of the Study:
- To review mechanisms of resistance to third-generation EGFR TKIs.
- To discuss novel EGFR TKIs designed to overcome C797S-mediated resistance.
- To provide perspectives on future challenges and directions in EGFR TKI development.
Main Methods:
- Analysis of resistance mechanisms associated with third-generation EGFR TKIs.
- Review of emerging allosteric and ATP-competitive inhibitors targeting EGFR C797S mutations.
- Evaluation of drug discovery, binding mechanisms, potency, and selectivity of novel inhibitors.
Main Results:
- Identification of key resistance mechanisms driven by the EGFR C797S mutation.
- Characterization of novel EGFR TKIs, including allosteric and ATP-competitive agents.
- Assessment of the potential of these new agents to overcome resistance and their binding characteristics.
Conclusions:
- The C797S mutation presents a significant challenge to EGFR TKI therapy in NSCLC.
- Novel EGFR TKIs targeting the C797S mutation are under development and show therapeutic potential.
- Further research is needed to address challenges and advance future EGFR TKI strategies.
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