Fluzoparib increases radiation sensitivity of non-small cell lung cancer (NSCLC) cells without BRCA1/2 mutation, a novel PARP1 inhibitor undergoing clinical trials

Propose Poly (ADP-ribose) polymerase 1 inhibitors were originally investigated as anti-cancer therapeutics with BRCA1/2 genes mutation. Here, we investigate the effectiveness of a novel PARP1 inhibitor fluzoparib, for enhancing the radiation sensitivity of NSCLC cells lacking BRCA1/2 mutation. Metho...

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Bibliographic Details
Published in:	Journal of cancer research and clinical oncology Vol. 146; no. 3; pp. 721 - 737
Main Authors:	Luo, Jing, Dai, Xinchi, Hu, Hua, Chen, Jie, Zhao, Lujun, Yang, Changyong, Sun, Jifeng, Zhang, Lianmin, Wang, Qian, Xu, Shilei, Xu, Yue, Liu, Ningbo, Ying, Guoguang, Wang, Ping
Format:	Journal Article
Language:	English
Published:	Berlin/Heidelberg Springer Berlin Heidelberg 01-03-2020 Springer Nature B.V
Subjects:	Animal models Animals Apoptosis Apoptosis - drug effects BRCA1 Protein BRCA2 Protein Cancer Research Carcinoma, Non-Small-Cell Lung Cell culture Cell Line, Tumor Cell Proliferation - drug effects Clinical trials Deoxyribonucleic acid DNA DNA damage DNA repair Flow cytometry Gene frequency Hematology Homologous recombination Humans Immunofluorescence Immunohistochemistry Internal Medicine Lung cancer Lung Neoplasms Medicine Medicine & Public Health Mice Mutation Non-small cell lung carcinoma Oncology Original Article – Clinical Oncology Poly(ADP-ribose) Polymerase 1 Poly(ADP-ribose) Polymerase Inhibitors - pharmacology Radiation Radiation Tolerance - drug effects Radiation-Sensitizing Agents - pharmacology Radiosensitization Ribose Small cell lung carcinoma Western blotting Xenograft Model Antitumor Assays Xenografts PARP1 inhibitor Radiosensitization NSCLC DNA damage response BRCAness
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Summary:	Propose Poly (ADP-ribose) polymerase 1 inhibitors were originally investigated as anti-cancer therapeutics with BRCA1/2 genes mutation. Here, we investigate the effectiveness of a novel PARP1 inhibitor fluzoparib, for enhancing the radiation sensitivity of NSCLC cells lacking BRCA1/2 mutation. Methods We used MTS assays, western blotting, colony formation assays, immunofluorescence staining, and flow cytometry to evaluate the radiosensitization of NSCLC cells to fluzoparib and explore the underlying mechanisms in vitro. Through BRCA1 and RAD50 genes knockdown, we established dysfunctional homologous recombination (HR) DNA repair pathway models in NSCLC cells. We next investigated the radiosensitization effect of fluzoparib in vivo using human NSCLC xenograft models in mice. The expression of PARP1 and BRCA1 in human NSCLC tumor samples was measured by immunohistochemistry. Furthermore, we sequenced HR-related gene mutations and analyzed their frequencies in advanced NSCLC. Results In vitro experiments in NSCLC cell lines along with in vivo experiments using an NSCLC xenograft mouse model demonstrated the radiosensitization effect of fluzoparib. The underlying mechanisms involved increased apoptosis, cell-cycle arrest, enhanced irradiation-induced DNA damage, and delayed DNA-damage repair. Immunohistochemical staining showed no correlation between the expression of PARP1 and BRCA1. Moreover, our sequencing results revealed high mutation frequencies for the BRCA1/2, CHEK2, ATR, and RAD50 genes. Conclusion The potential therapeutic value of fluzoparib for increasing the radiation sensitivity of NSCLC is well confirmed. Moreover, our findings of high mutation frequencies among HR genes suggest that PARP1 inhibition may be an effective treatment strategy for advanced non-small cell lung cancer patients.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0171-5216 1432-1335
DOI:	10.1007/s00432-019-03097-6