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Magnolin overcomes EGFR TKI resistance in NSCLC by modulation of NDRG1-NRG2-HECW1 pathway

Acta Pharmacologica Sinica (2025)Cite this article

Abstract

Resistance of non-small cell lung cancer (NSCLC) to EGFR tyrosine kinase inhibitors (TKIs) limits the efficacy and leads to disease progression with mechanisms such as activation of autophagy in tumor cells, but the current therapeutic strategies are unable to intervene in this mechanism. Magnolin (Mag), a naturally derived compound, has garnered significant interest due to its potential antitumor properties. Through virtual screening methods, Mag was identified as a compound with potential to regulate molecular pathways closely related to drug resistance mechanisms. In this study, we investigated the ability of Mag to enhance EGFR TKI efficacy in resistant NSCLC. Afatinib-resistant cell line (HCC827AR) was established by continuously exposing HCC827 cells to afatinib (4 µM) for 6 months. Medium containing 4 µM afatinib was refreshed every 48 h. By conducting RNA sequencing (RNA-seq) and exome sequencing on HCC827AR cells, NRG2 was identified as a core-enriched gene. We demonstrated that Mag directly bound to the TYR112 residue of NDRG1, stabilizing its expression and preventing its degradation. This interaction upregulated NDRG1, which in turn promoted its interaction with the E3 ubiquitin ligase HECW1, facilitating the ubiquitination and degradation of NRG2 at lysine 223 (K223). By targeting the NDRG1-NRG2-HECW1 pathway, Mag uniquely inhibited autophagy and restored the sensitivity of HCC827AR cells to EGFR TKIs, thereby reversing resistance. In vivo, the combined treatment with Mag (30 mg· kg−1 ·d−1, i.g.) and Afa (10 mg· kg−1 ·d−1, i.g.) significantly reduced tumor growth in patient-derived xenografts without inducing major toxicity. This study unravels the intricate role of NDRG1 in modulating NRG2 via HECW1. The results not only illuminate Mag’s promising potential as an adjunctive therapy to surmount EGFR TKI resistance, but also underscore the significant therapeutic potential of targeting the NDRG1-NRG2-HECW1 pathway as a novel strategy to reverse EGFR TKI resistance in NSCLC.

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Fig. 1: NRG2 is related to EGFR TKI resistance in NSCLC.
Fig. 2: NRG2 was inhibited by Mag in EGFR TKI resistance.
Fig. 3: NDRG1 expression was negatively correlated with NRG2.
Fig. 4: Mag enhanced the NDRG1-HECW1-NRG2 complex, leading to the degradation of NRG2 in NSCLC.
Fig. 5: NDRG1 was another key regulator of EGFR TKI resistance in NSCLC.
Fig. 6: Safety and antitumor potential of Mag in PDX of NSCLC.
Fig. 7: Mag targeted the NDRG1/NRG2 axis to overcome EGFR TKI resistance in NSCLC.

Data availability

The RNA microarray datasets generated in this study were deposited into the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database under accession number GSE277007. The RNA-seq and microarray datasets demonstrated in Fig. 3b were downloaded from NCBI’s GEO: GSE121634, GSE193258, and GSE277007.

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Funding

This study was supported by National Natural Science Foundation of China (Grant no. 82374095), Shaanxi Province Science Fund for Distinguished Young Scholars (2023-JC-JQ-59), the Shaanxi Province Science and Technology Development Plan Project (2022ZDLSF05-05).

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Authors and Affiliations

  1. Department of Medical Oncology, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, China

    Qing Wu, Wen-juan Tang & Yan-min Zhang

  2. School of Pharmacy, Health Science Center, Xi’an Jiaotong University, Xi’an, 710061, China

    Qing Wu, Qi Su, Man Zhu, Tian-feng Yang, Wen-juan Tang, Yu Hu, Jia-yan Ren, Xiu-hong Peng, Su-yu Zhang & Yan-min Zhang

  3. State Key Laboratory of Shaanxi for Natural Medicines Research and Engineering, Xi’an, 710061, China

    Qing Wu, Qi Su, Man Zhu, Tian-feng Yang, Wen-juan Tang, Yu Hu, Jia-yan Ren, Xiu-hong Peng, Su-yu Zhang & Yan-min Zhang

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  1. Qing Wu
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  2. Qi Su
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  3. Man Zhu
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Contributions

QW: Methodology, Investigation, Validation, Original draft Writing. QS, MZ, TFY, and WJT: Investigation, Review & editing. YH: Methodology, Validation. JYR: Conceptualization, Formal analysis. XHP: Validation, Formal analysis. SYZ: Investigation, Formal analysis. YMZ: Conceptualization, Funding acquisition, Supervision, Review & editing.

Corresponding author

Correspondence to Yan-min Zhang.

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The authors declare no competing interests.

Ethical approval

This human study was approved by the Shanghai Zhuoli Biotech Company Review Board (ZLL-15-01) and performed in accordance with the Declaration of Helsinki. The animal experimental procedures were approved by the Biomedical Ethics Committee of the Xi’an Jiaotong University Health Science Center (approval number: XJTUAE2023-2214).

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Wu, Q., Su, Q., Zhu, M. et al. Magnolin overcomes EGFR TKI resistance in NSCLC by modulation of NDRG1-NRG2-HECW1 pathway. Acta Pharmacol Sin (2025). https://doi.org/10.1038/s41401-025-01670-z

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