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PARP inhibitor niraparib as a radiosensitizer promotes antitumor immunity of radiotherapy in EGFR-mutated non-small cell lung cancer

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Abstract

Background

Poly-(ADP-Ribose)-Polymerase inhibitors (PARPi) were reported as radiosensitizers in non-small cell lung cancer (NSCLC) with wide-type epidermal growth factor receptor (EGFR), but the effects of radiation combined with PARPi were not investigated in EGFR-mutated NSCLC. Moreover, the underlying mechanisms were not well examined. This study aimed to study the efficacy of radiation combined with niraparib in EGFR-mutated NSCLC and explore their influence on the immune system.

Methods

Clone formation and apoptosis assay were conducted to explore the effects of niraparib and radiation. Immunofluorescence was conducted to detect the double-strand DNA breaks. Real-time PCR and immunoblotting were employed to evaluate the activation of STING/TBK1/TRF3 pathway and the expression levels of interferon β, CCL5 and CXCL10. Immunocompetent mice model bearing with subcutaneous Lewis lung cancer was established to confirm the results in vivo.

Results

Niraparib and radiation were synergistic to inhibit tumor both in vitro and in vivo. Radiation plus niraparib could activate anti-tumor immunity, which appeared as increased CD8+ T lymphocytes and activated STING/TBK1/IRF3 pathway.

Conclusion

PARPi not only as a radiosensitizer inhibited EGFR-mutated NSCLC tumor growth, but also cooperated with radiation to promote anti-tumor immune responses.

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Availability of data and materials

The data used and analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

NSCLC:

Non-small cell lung cancer

PARPi:

Poly-(ADP-Ribose)-Polymerase inhibitors

RT:

Radiotherapy

EGFR:

Epidermal growth factor receptor

ds-DNA:

Double strand DNA

ss-DNA:

Single strand DNA

LLC:

Lung Lewis carcinoma

ICBs:

Immune checkpoint blockades

IFN β:

Interferon β

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Acknowledgements

This work was supported by Zai Lab Co., Ltd for their donation of the niraparib (ZL-2306).

Funding

This study was supported by the National Natural Science Foundation of China (81773236, 81800429 and 81972852), Key Research & Development Project of Hubei Province (2020BCA069), Nature Science Foundation of Hubei Province (2020CFB612), Health Commission of Hubei Province Medical Leading Talent Project, Young and Middle-Aged Medical Backbone Talents of Wuhan (WHQG201902), Application Foundation Frontier Project of Wuhan (2020020601012221), Zhongnan Hospital of Wuhan University Science, Technology and Innovation Seed Fund (znpy2019001, znpy2019048, and ZNJC201922), and Chinese Society of Clinical Oncology TopAlliance Tumor Immune Research Fund (Y-JS2019-036).

Author information

Author notes

  1. N. Zhang and Y. Gao contributed equally as first authors to this study.

Authors and Affiliations

  1. Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China

    N. Zhang, Y. Gao, Z. Zeng, Y. Luo, X. Jiang, J. Zhang, J. Li, J. Zhang & C. Xie

  2. Hubei Key Laboratory of Tumour Biological Behaviors, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China

    J. Zhang & C. Xie

  3. Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China

    J. Zhang & C. Xie

  4. Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China

    Y. Gong

  5. Human Genetics Resource Preservation Center of Hubei Province, Human Genetics Resource Preservation Center of Wuhan University, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China

    Y. Gong

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  1. N. Zhang
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Contributions

NZ, JZ, YGong and CX designed the study, analyzed the data and wrote this manuscript. NZ, YGao, YL and JL performed the study. NZ, ZZ, XJ and JZ analyzed the date. All authors reviewed and agreed to the publication of the manuscript.

Corresponding authors

Correspondence to Y. Gong or C. Xie.

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The authors declare that no conflict of interests exists in this research project.

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All procedures performed in studies involving animals were approved by the Institutional Animal Care and Use Committee of Wuhan University. This article does not contain any studies involving human participants performed by any of the authors.

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Informed consent was not applicable, and animal experiments were approved by IACUC.

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Zhang, N., Gao, Y., Zeng, Z. et al. PARP inhibitor niraparib as a radiosensitizer promotes antitumor immunity of radiotherapy in EGFR-mutated non-small cell lung cancer. Clin Transl Oncol 23, 1827–1837 (2021). https://doi.org/10.1007/s12094-021-02591-z

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