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Mechanism of targeting the mTOR pathway to regulate ferroptosis in NSCLC with different EGFR mutations

  • Authors:
    • Chunjiao Wu
    • Rui Zhong
    • Tianxue Wei
    • Yulong Jin
    • Chunying He
    • Hui Li
    • Ying Cheng
  • View Affiliations / Copyright

    Affiliations: Phase I Clinical Research Ward, Jilin Cancer Hospital, Changchun, Jilin 130000, P.R. China, Translational Cancer Research Lab, Jilin Cancer Hospital, Changchun, Jilin 130000, P.R. China, Biobank, Jilin Cancer Hospital, Changchun, Jilin 130000, P.R. China
    Copyright: © Wu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 298
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    Published online on: May 1, 2024
       https://doi.org/10.3892/ol.2024.14431
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Abstract

Patients with non‑small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR)‑activating mutations can be treated with EGFR‑tyrosine kinase inhibitors (TKIs). Although EGFR‑TKI‑targeted drugs bring survival promotion in patients with EGFR mutations, drug resistance is inevitable, so it is urgent to explore new treatments to overcome drug resistance. In addition, wild‑type EGFR lacks targeted drugs, and new targeted therapies need to be explored. Ferroptosis is a key research direction for overcoming drug resistance. However, the role and mechanism of regulating ferroptosis in different EGFR‑mutant NSCLC types remains unclear. In the present study, H1975 (EGFR T790M/L858R mutant), A549 (EGFR wild‑type) and H3255 (EGFR L858R mutant) NSCLC cell lines were used. The expression of ferroptosis markers in these cell lines was detected using western blotting and reverse transcription‑quantitative PCR. Cell viability was determined using the MTT assay and reactive oxygen species (ROS) levels were measured using flow cytometry. The results showed that, compared with EGFR wild‑type/sensitive mutant cells, EGFR‑resistant mutant cells were more sensitive to the ferroptosis inducer, erastin. Furthermore, the mammalian target of rapamycin (mTOR) inhibitor, everolimus (RAD001), induced cell death in all three cell lines in a dose‑dependent manner. The ferroptosis inhibitor, ferrostatin‑1, could reverse cell death in EGFR‑resistant mutant and EGFR wild‑type cells induced by RAD001, but could not reverse cell death in EGFR‑sensitive mutant cells. Compared with EGFR wild‑type/sensitive mutant cells, EGFR‑resistant mutant cells were more sensitive to RAD001 combined with erastin. In addition, a high‑dose of RAD001 reduced the expression levels of ferritin heavy‑chain polypeptide 1 (FTH1), glutathione peroxidase 4 (GPX4) and ferroportin and significantly increased ROS and malondialdehyde (MDA) levels in EGFR‑resistant mutant and EGFR wild‑type cells. In the present study, GPX4 inhibitor only or combined with RAD001 inhibited the AKT/mTOR pathway in EGFR‑resistant mutant cells. Therefore, the results of the present study suggested that inhibition of the mTOR pathway may downregulate the expression of ferroptosis‑related proteins in EGFR‑resistant and EGFR wild‑type NSCLC cells, increase the ROS and MDA levels and ultimately induce ferroptosis.
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Copy and paste a formatted citation
Spandidos Publications style
Wu C, Zhong R, Wei T, Jin Y, He C, Li H and Cheng Y: Mechanism of targeting the mTOR pathway to regulate ferroptosis in NSCLC with different EGFR mutations. Oncol Lett 28: 298, 2024.
APA
Wu, C., Zhong, R., Wei, T., Jin, Y., He, C., Li, H., & Cheng, Y. (2024). Mechanism of targeting the mTOR pathway to regulate ferroptosis in NSCLC with different EGFR mutations. Oncology Letters, 28, 298. https://doi.org/10.3892/ol.2024.14431
MLA
Wu, C., Zhong, R., Wei, T., Jin, Y., He, C., Li, H., Cheng, Y."Mechanism of targeting the mTOR pathway to regulate ferroptosis in NSCLC with different EGFR mutations". Oncology Letters 28.1 (2024): 298.
Chicago
Wu, C., Zhong, R., Wei, T., Jin, Y., He, C., Li, H., Cheng, Y."Mechanism of targeting the mTOR pathway to regulate ferroptosis in NSCLC with different EGFR mutations". Oncology Letters 28, no. 1 (2024): 298. https://doi.org/10.3892/ol.2024.14431
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Spandidos Publications style
Wu C, Zhong R, Wei T, Jin Y, He C, Li H and Cheng Y: Mechanism of targeting the mTOR pathway to regulate ferroptosis in NSCLC with different EGFR mutations. Oncol Lett 28: 298, 2024.
APA
Wu, C., Zhong, R., Wei, T., Jin, Y., He, C., Li, H., & Cheng, Y. (2024). Mechanism of targeting the mTOR pathway to regulate ferroptosis in NSCLC with different EGFR mutations. Oncology Letters, 28, 298. https://doi.org/10.3892/ol.2024.14431
MLA
Wu, C., Zhong, R., Wei, T., Jin, Y., He, C., Li, H., Cheng, Y."Mechanism of targeting the mTOR pathway to regulate ferroptosis in NSCLC with different EGFR mutations". Oncology Letters 28.1 (2024): 298.
Chicago
Wu, C., Zhong, R., Wei, T., Jin, Y., He, C., Li, H., Cheng, Y."Mechanism of targeting the mTOR pathway to regulate ferroptosis in NSCLC with different EGFR mutations". Oncology Letters 28, no. 1 (2024): 298. https://doi.org/10.3892/ol.2024.14431
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