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Updated: Mar 22, 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
NF-κB-driven suppression of FOXO3a contributes to EGFR mutation-independent gefitinib resistance
Ching-Feng Chiu1, Yi-Wen Chang1, Kuang-Tai Kuo2
1National Institute of Cancer Research, National Health Research Institutes, Miaoli County 35053, Taiwan;
Abstract:
Therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs, such as gefitinib or erlotinib) significantly prolongs survival time for patients with tumors harboring an activated mutation on EGFR; however, up to 40% of lung cancer patients exhibit acquired resistance to EGFR-TKIs with an unknown mechanism. FOXO3a, a transcription factor of the forkhead family, triggers apoptosis, but the mechanistic details involved in EGFR-TKI resistance and cancer stemness remain largely unclear. Here, we observed that a high level of FOXO3a was correlated with EGFR mutation-independent EGFR-TKI sensitivity, the suppression of cancer stemness, and better progression-free survival in lung cancer patients. The suppression of FOXO3a obviously increased gefitinib resistance and enhanced the stem-like properties of lung cancer cells; consistent overexpression of FOXO3a in gefitinib-resistant lung cancer cells reduced these effects. Moreover, we identified that miR-155 targeted the 3'UTR of FOXO3a and was transcriptionally regulated by NF-κB, leading to repressed FOXO3a expression and increased gefitinib resistance, as well as enhanced cancer stemness of lung cancer in vitro and in vivo. Our findings indicate that FOXO3a is a significant factor in EGFR mutation-independent gefitinib resistance and the stemness of lung cancer, and suggest that targeting the NF-κB/miR-155/FOXO3a pathway has potential therapeutic value in lung cancer with the acquisition of resistance to EGFR-TKIs.
Insights
High FOXO3a levels improve sensitivity to EGFR-TKIs in lung cancer, suppressing stemness and resistance. Targeting the NF-κB/miR-155/FOXO3a pathway may overcome acquired resistance to these therapies.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) improve survival in EGFR-mutated lung cancer.
- Acquired resistance to EGFR-TKIs occurs in up to 40% of patients, with mechanisms often unclear.
- The role of FOXO3a in EGFR-TKI resistance and cancer stemness is not well understood.
Purpose of the Study:
- To investigate the role of FOXO3a in acquired resistance to EGFR-TKIs and its association with cancer stemness in lung cancer.
- To elucidate the molecular mechanisms underlying FOXO3a regulation and its impact on therapeutic response.
Main Methods:
- Correlation analysis of FOXO3a levels with clinical outcomes in lung cancer patients.
- In vitro and in vivo experiments involving manipulation of FOXO3a expression in lung cancer cells.
- Investigation of the regulatory relationship between NF-κB, miR-155, and FOXO3a.
Main Results:
- High FOXO3a levels correlated with EGFR mutation-independent EGFR-TKI sensitivity, suppressed cancer stemness, and improved progression-free survival.
- FOXO3a suppression increased gefitinib resistance and enhanced cancer stem-like properties, while its overexpression reversed these effects.
- NF-κB transcriptionally regulated miR-155, which targeted FOXO3a, leading to repressed FOXO3a expression, increased gefitinib resistance, and enhanced cancer stemness.
Conclusions:
- FOXO3a plays a critical role in EGFR mutation-independent gefitinib resistance and lung cancer stemness.
- The NF-κB/miR-155/FOXO3a axis is a key pathway regulating acquired resistance to EGFR-TKIs.
- Targeting the NF-κB/miR-155/FOXO3a pathway presents a potential therapeutic strategy for overcoming acquired resistance in lung cancer.
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