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PARP1 promotes EGFR-TKI drug-resistance via PI3K/AKT pathway in non-small-cell lung cancer

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Abstract

Purpose

Tyrosine kinase inhibitor (TKI) resistance is the main type of drug resistance in lung cancer patients with epidermal growth factor receptor (EGFR) mutations, but its underlying mechanism remains unclear. The purpose of this work was to investigate the mechanism by which PARP1 regulates EGFR-TKI resistance to identify potential targets for combating drug resistance.

Methods

The GEO databases, TCGA databases, western blot and qPCR studies were used to investigate the expression of PARP1 in lung cancer cells and tissues and its correlation with the prognosis of lung cancer. The expression of PARP1 in lung cancer TKI resistant cell PC9-ER and TKI sensitive cell PC9 was analyzed by qPCR and western blot. After knocking down of PARP1, CCK-8 assays, colony formation, flow cytometry were used to investigate its impact on erlotinib sensitivity, cell survival, cell cycle, and apoptosis. RNA-seq was used to investigate the mechanism by which PARP1 participates in EGFR-TKI resistance, and the results were validated in vitro and in vivo studies.

Results

PARP1 was highly expressed in both lung cancer tissues and cells. Subsequently, increased PARP1 expression was observed in PC9-ER compared with its parental cell line. Knockdown of PARP1 increased erlotinib sensitivity, promoted cell apoptosis, and suppressed cell growth. RNA-seq and previous studies have shown that the PI3K/AKT/mTOR/P70S6K pathway is involved in PARP1-mediated TKI resistance, and these results were confirmed by Western blot in vitro and in vivo.

Conclusion

PARP1 may serve as a potential therapeutic target for reversing EGFR-TKI resistance in NSCLC via the PI3K/AKT/mTOR/P70S6K pathway.

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Data availability

No datasets were generated or analysed during the current study.

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Acknowledgements

Not applicable.

Funding

This study was supported by grants from Chongqing Yuzhong District Science and Technology Committee (grant number 20190118).

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Authors and Affiliations

  1. Department of Oncology, The Affiliated Hospital of Southwest Medical University, No. 25 Taiping Street, Jiangyang District Luzhou, Sichuan, 646000, China

    Xianping Xu & Zhibin Luo

  2. Department of Oncology, Chongqing Genaral Hospital, No.118, Xingguang Avenue, Liangjiang New Area, Chongqing, 401147, China

    Xianping Xu, Yu Liu, Wei Wei, Linqiong Zhao & Zhibin Luo

  3. Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Gaotanyan Road Street, Shapingba District, Chongqing, 400038, China

    Qiang Gong & Le Ma

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  1. Xianping Xu
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  5. Wei Wei
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Contributions

LZB: Contributed to the conception of the study; XXP: performed the experiment and wrote this manuscript; WW: contributed significantly to analysis and manuscript preparation; YL, GQ and ML: performed collecting clinical data and analyzing it; ZLQ : helped perform the analysis with constructive discussions. All authors contributed to the article and approved the submitted version.

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Correspondence to Zhibin Luo.

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Xu, X., Liu, Y., Gong, Q. et al. PARP1 promotes EGFR-TKI drug-resistance via PI3K/AKT pathway in non-small-cell lung cancer. Cancer Chemother Pharmacol (2024). https://doi.org/10.1007/s00280-024-04668-2

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