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A novel combination treatment of antiADAM17 antibody and erlotinib to overcome acquired drug resistance in non-small cell lung cancer through the FOXO3a/FOXM1 axis

Cellular and Molecular Life Sciences volume 79, Article number: 614 (2022) Cite this article

Abstract

After the identification of specific epidermal growth factor receptor (EGFR)-activating mutations as one of the most common oncogenic driver mutations in non-small cell lung cancer (NSCLC), several EGFR-tyrosine kinase inhibitors (EGFR-TKIs) with different clinical efficacies have been approved by various health authorities in the last two decades in targeting NSCLC harboring specific EGFR-activating mutations. However, most patients whose tumor initially responded to the first-generation EGFR-TKI developed acquired resistance. In this study, we developed a novel combination strategy, “antiADAM17 antibody A9(B8) + EGFR-TKIs”, to enhance the efficacy of EGFR-TKIs. The addition of A9(B8) was shown to restore the effectiveness of erlotinib and overcome acquired resistance. We found that when A9(B8) antibody was treated with erlotinib or gefitinib, the combination treatment synergistically increased apoptosis in an NSCLC cell line and inhibited tumor growth in vivo. Interestingly, the addition of A9(B8) could only reduce the survival of the erlotinib-resistant NSCLC cell line and inhibit the growth of erlotinib-resistant tumors in vivo but not gefitinib-resistant cells. Furthermore, we revealed that A9(B8) overcame erlotinib resistance through the FOXO3a/FOXM1 axis and arrested the cell cycle at the G1/S phase, resulting in the apoptosis of cancer cells. Hence, this study establishes a novel, promising strategy for overcoming acquired resistance to erlotinib through the FOXO3a/FOXM1 axis by arresting the cell cycle at the G1/S phase.

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Data availability

All the data supporting the findings of this study are available within the paper.

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Acknowledgements

We would like to thank all the staff in the Animal Facility, Biological Imaging and Stem Cell Core and Genomics and Bioinformatics Core at the Faculty of Health Sciences, University of Macau, for providing histopathology equipment and technical support.

Funding

This study was supported by the Science and Technology Development Fund (FDCT) Macau SAR (File no. 0055/2019/A1 and 0027/2022/A1). Junnan Li and Qiushuang Wu were in receipt of the UM PhD Assistantship. Pengchen Chen and Guo Libin were in receipt of PhD funding from the FDCT and the Faculty of Health Sciences, University of Macau. Ka Weng Leong was in receipt of the research assistant funding from the FDCT.

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Authors and Affiliations

  1. Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau SAR

    Junnan Li, Pengchen Chen, Qiushuang Wu, Libin Guo, Ka Weng Leong & Hang Fai Kwok

  2. MoE Frontiers Science Center for Precision Oncology, University of Macau, Avenida de Universidade, Taipa, Macau SAR

    Hang Fai Kwok

  3. Department of Biomedical Sciences, Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau SAR

    Hang Fai Kwok

  4. Department of Pathology, Kiang Wu Hospital, Macau, Macau SAR

    Kin Iong Chan

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  1. Junnan Li
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  2. Pengchen Chen
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  3. Qiushuang Wu
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  4. Libin Guo
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  5. Ka Weng Leong
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Contributions

JL carried out the experiments; JL, KIC, PC, QW, LG, and HFK analyzed and interpreted the results; JL, KWL and HFK designed and drafted the manuscript; HFK secured the funding, participated in the design of the study and revised the manuscript.

Corresponding author

Correspondence to Hang Fai Kwok.

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The authors declare no conflicts of interest.

Ethics approval

This study was performed with the approval of the Medical Ethics Committee of Kiang Wu Hospital and Faculty of Health Sciences University of Macau.

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All clinical samples were collected after written informed consent was obtained from the patients included in the study.

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Li, J., Chen, P., Wu, Q. et al. A novel combination treatment of antiADAM17 antibody and erlotinib to overcome acquired drug resistance in non-small cell lung cancer through the FOXO3a/FOXM1 axis. Cell. Mol. Life Sci. 79, 614 (2022). https://doi.org/10.1007/s00018-022-04647-x

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  • DOI: https://doi.org/10.1007/s00018-022-04647-x

Keywords

  • Precision oncology
  • Drug target
  • Small molecule
  • Antibody therapy
  • Cell death