Combined use of 177Lu‐DOTATATE peptide receptor radionuclide therapy and fluzoparib for treatment of well‐differentiated neuroendocrine tumors: A preclinical study

Peptide receptor radionuclide therapy (177Lu‐DOTATATE) causes DNA strand breaks and has been validated for well‐differentiated neuroendocrine tumor treatment. Poly‐(ADP‐ribose)‐polymerase inhibitors have also been used for malignant tumors with deficient DNA repair. We aimed to determine whether the poly‐(ADP‐ribose)‐polymerase inhibitor fluzoparib could enhance the anti‐tumor effects of 177Lu‐DOTATATE in neuroendocrine tumor cells and xenografts. The neuroendocrine characteristics of NCI‐H727 bronchial carcinoid cells were evaluated by immunofluorescence staining. The synergistic effects of fluzoparib and 177Lu‐DOTATATE were evaluated by cell proliferation and flow cytometry assays. Tumor response and the side effects of combination therapy were also assessed in xenograft mice treated with 77Lu‐DOTATATE and fluzoparib alone or in combination. Somatostatin receptors were specifically expressed in NCI‐H727 cells and tumor xenografts. 177Lu‐DOTATATE (22.20 MBq mL–1) and fluzoparib (50 µm) inhibited cell proliferation by 16.6% and 35.6%, respectively, compared to 73.2% in cells treated with their combination. Tumor cell proliferation was significantly suppressed by 177Lu‐DOTATATE (22.20 MBq mL–1, 4.4‐fold) and fluzoparib (50 µm, 2.1‐fold). 177Lu‐DOTATATE caused cell cycle arrest mainly at G1 phase, whereas fluzoparib caused arrest at G2/M phase, and combined treatment with both agents caused cell cycle arrest at G1 phase, similar to 177Lu‐DOTATATE alone. The volume of tumor xenografts was reduced by 18.6% in mice receiving combined treatment, compared to 4.9% and 11.4% in mice treated with 177Lu‐DOTATATE or fluzoparib alone. Fluzoparib can potentiate the anti‐tumor effect of 177Lu‐DOTATATE in NCI‐H727 cells in a synergistic manner by arresting the cell cycle at G1 phase. Further preclinical and clinical studies are warranted to validate these findings. In the present study, we aimed to characterize NCI‐H727 cell lines and xenograft with neuroendocrine features and to identify appropriate models for evaluating the anti‐tumor activity of combination regimens incorporating somatostatin receptor 2‐targeted peptide receptor radionuclide therapy (PRRT). This in vitro and in vivo study showed that 177Lu‐DOTATATE combining with fluzoparib exerts synergic effects and improve the treatment outcomes in well‐differentiated neuroendocrine tumors (NETs). The study sheds light on the combination of PRRT and PARP‐I in the treatment of NET, which may serve as a novel treatmen