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Growth Suppression in Lung Cancer Cells Harboring EGFR-C797S Mutation by Quercetin
Kuo-Yen Huang1, Tong-Hong Wang2,3, Chin-Chuan Chen3,4
1Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei 11490, Taiwan.
Abstract:
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are approved treatments for non-small-cell lung cancer (NSCLC) patients harboring activating EGFR mutations. The EGFR C797S mutation is one of the known acquired-resistance mutations to the latest third-generation TKIs. At present, there are no clear options for treating patients who acquire resistance to third-generation TKIs. The acquisition of the EGFR C797S mutation was shown to upregulate the expression of AXL, a receptor tyrosine kinase of the TAM (TYRO3-AXL-MER) family, and the suppression of AXL is effective in reducing the growth of NSCLC cells harboring EGFR C797S. As quercetin was recently shown to inhibit AXL, quercetin may be effective in treating NSCLC cells harboring the EGFR C797S mutation. In this work, the cytotoxic effects of quercetin and its ability to inhibit tumor growth were examined in TKI-resistant NSCLC cells harboring the EGFR C797S mutation. We demonstrated that quercetin exhibited potent cytotoxic effects on NSCLC cells harboring the EGFR C797S mutation by inhibiting AXL and inducing apoptosis. Quercetin inhibited the tumor growth of xenografted NSCLC cells harboring the EGFR C797S mutation and appeared to act synergistically with brigatinib to inhibit of tumor growth in vivo. In summary, herein, we revealed that quercetin is an effective inhibitor for the treatment of non-small-cell lung cancer harboring the EGFR C797S mutation.
Insights
Quercetin shows promise in treating non-small-cell lung cancer (NSCLC) with EGFR C797S mutations. This natural compound inhibits AXL, reduces tumor growth, and induces apoptosis, offering a new therapeutic avenue for TKI-resistant lung cancer.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are standard treatments for non-small-cell lung cancer (NSCLC) with activating EGFR mutations.
- Acquired resistance to third-generation TKIs, often due to the EGFR C797S mutation, presents a significant clinical challenge with limited treatment options.
- The EGFR C797S mutation upregulates AXL receptor tyrosine kinase, and AXL inhibition has shown efficacy in reducing NSCLC cell growth.
Purpose of the Study:
- To investigate the potential of quercetin as a therapeutic agent for NSCLC cells harboring the EGFR C797S resistance mutation.
- To evaluate the cytotoxic effects and tumor growth inhibitory capabilities of quercetin in this specific NSCLC context.
- To explore the mechanism of action, including AXL inhibition and apoptosis induction by quercetin.
Main Methods:
- Assessment of quercetin's cytotoxic effects on NSCLC cells with EGFR C797S mutations.
- In vivo studies using xenograft models to evaluate quercetin's tumor growth inhibition.
- Examination of quercetin's effect on AXL expression and induction of apoptosis.
- Evaluation of synergistic effects of quercetin with brigatinib in vivo.
Main Results:
- Quercetin demonstrated potent cytotoxic effects against NSCLC cells harboring the EGFR C797S mutation.
- Quercetin effectively inhibited tumor growth in xenograft models of EGFR C797S-mutated NSCLC.
- The mechanism involved AXL inhibition and induction of apoptosis.
- Quercetin exhibited synergistic effects with brigatinib in suppressing tumor growth in vivo.
Conclusions:
- Quercetin is an effective inhibitor for treating non-small-cell lung cancer with the EGFR C797S mutation.
- Quercetin's ability to inhibit AXL and induce apoptosis provides a novel therapeutic strategy.
- Quercetin holds potential as a treatment option for patients resistant to third-generation TKIs, possibly in combination therapies.
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