Related Experiment Video
Updated: Aug 22, 2025
Establishment and Characterization of Three Afatinib-resistant Lung Adenocarcinoma PC-9 Cell Lines Developed with Increasing Doses of Afatinib
Published on: June 26, 2019
MNK/eIF4E inhibition overcomes anlotinib resistance in non-small cell lung cancer
1Department of Oncology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, China.
Abstract:
Anlotinib is approved for refractory cases in advanced non-small-cell lung cancer (NSCLC). This is a novel oral multitarget tyrosine kinase inhibitor, but patients inevitably face prospects of drug resistance during the treatment process. Using anlotinib-resistant NSCLC models, this work investigated the underlying molecular mechanism and systematically addressed the issue of anlotinib resistance. We demonstrated that expression and activity of eukaryotic translation initiation factor 4E (eIF4E) were upregulated in NSCLC cells due to prolonged exposure to anlotinib. eIF4E depletion resulted in significant effects to anlotinib-resistant cells, showing proliferation inhibition and apoptosis inducement. We further showed that MAP kinase interacting serine/threonine kinase (MNK)-dependent eIF4E inhibition by cercosporamide was active against anlotinib-resistant cells and significantly augmented anlotinib's efficacy in parental NSCLC cells. Importantly, observations from in-vitro experiments are consistent in in vivo anlotinib-resistant and anlotinib-sensitive NSCLC cancer xenograft mouse models. Our work is the first to reveal that eIF4E is involved intimately in anlotinib resistance development in NSCLC, and this eIF4E activation can be reversed by cercosporamide or other MNK inhibitors.
Insights
Anlotinib resistance in non-small-cell lung cancer (NSCLC) is linked to increased eukaryotic translation initiation factor 4E (eIF4E). Inhibiting eIF4E with cercosporamide overcomes resistance and enhances anlotinib efficacy in NSCLC models.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Anlotinib is an oral multitarget tyrosine kinase inhibitor for advanced non-small-cell lung cancer (NSCLC).
- Drug resistance is a significant challenge during anlotinib treatment, necessitating investigation into underlying mechanisms.
Purpose of the Study:
- To investigate the molecular mechanisms of anlotinib resistance in NSCLC.
- To identify therapeutic strategies to overcome anlotinib resistance.
Main Methods:
- Utilized anlotinib-resistant NSCLC cell and xenograft mouse models.
- Assessed the role of eukaryotic translation initiation factor 4E (eIF4E) and its regulation by MAP kinase interacting serine/threonine kinase (MNK).
- Evaluated the efficacy of eIF4E inhibition using cercosporamide.
Main Results:
- Upregulation of eIF4E expression and activity was observed in anlotinib-resistant NSCLC cells.
- Depletion of eIF4E inhibited proliferation and induced apoptosis in resistant cells.
- Cercosporamide, an MNK-dependent eIF4E inhibitor, demonstrated activity against resistant cells and potentiated anlotinib efficacy in both resistant and sensitive NSCLC models.
Conclusions:
- eIF4E plays a critical role in the development of anlotinib resistance in NSCLC.
- Targeting eIF4E with MNK inhibitors like cercosporamide is a promising strategy to overcome anlotinib resistance and improve treatment outcomes in NSCLC.
More Related Videos
09:38Establishing 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
06:51Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer
Published on: July 21, 2018
Related Concept Videos
02:38Mitogens and the Cell Cycle
02:56Treatment Resistant Cancers