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

Abstract

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.

• Authors: Jing Luo, Xinchi Dai, Hua Hu, Jie Chen, Lujun Zhao, Changyong Yang, Jifeng Sun, Lianmin Zhang, Qian Wang, Shilei Xu, Yue Xu, Ningbo Liu, Guoguang Ying, Ping Wang
• Journal: Journal of cancer research and clinical oncology (J Cancer Res Clin Oncol) Vol. 146 Issue 3 Pg. 721-737 (Mar 2020) ISSN: 1432-1335 [Electronic] Germany
• PMID: 31786739 (Publication Type: Journal Article)

Chemical References

• BRCA1 Protein
• BRCA1 protein, human
• BRCA2 Protein
• Poly(ADP-ribose) Polymerase Inhibitors
• Radiation-Sensitizing Agents

Topics

• Animals
• Apoptosis (drug effects)
• BRCA1 Protein
• BRCA2 Protein
• Carcinoma, Non-Small-Cell Lung
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Humans
• Lung Neoplasms
• Mice
• Mutation
• Poly(ADP-ribose) Polymerase Inhibitors (pharmacology)
• Radiation Tolerance (drug effects)
• Radiation-Sensitizing Agents (pharmacology)
• Xenograft Model Antitumor Assays