DNA-PKcs inhibitors sensitize neuroendocrine tumor cells to peptide receptor radionuclide therapy in vitro and in vivo

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Abstract

Background: Peptide receptor radionuclide therapy (PRRT) increases progression-free survival and quality of life of neuroendocrine tumor (NET) patients, however complete cures are rare and dose-limiting toxicity has been reported. PRRT induces DNA damage of which DNA double strand breaks (DSBs) are the most cytotoxic. DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a key player in DSB repair and its inhibition therefore is a potential way to enhance PRRT efficacy without increasing the dosage. Methods: We analyzed effects of combining PRRT and DNA-PKcs inhibitor AZD7648 on viability, cell death and clonogenic survival on SSTR2-expressing cell lines BON1-SSTR2, GOT1 and NCI-H69. Therapy-induced DNA damage response was assessed by analyzing DSB foci levels and cell cycle distributions. In vivo efficacy was investigated in BON1-SSTR2 and NCI-H69 xenografted mice and hematologic and renal toxicity were monitored by blood counts, creatinine levels and analyzing renal morphology. Results: Combining PRRT and AZD7648 significantly decreased viability of BON1-SSTR2, GOT1 and NCI-H69 cells and induced cell death in GOT1 and BON1-SSTR2 cells. A strong effect of AZD7648 on PRRT-induced DSB repair was found. In GOT1 cells, this was accompanied by induction of cell cycle blocks. However, BON1-SSTR2 cells were unable to fully arrest their cell cycle and polyploid cells with high DNA damage levels were detected. In vivo, AZD7648 significantly sensitized BON1-SSTR2 and NCI-H69 xenograft models to PRRT. In addition, combination therapy did not induce significant changes in body weight, blood composition, plasma creatinine levels and renal morphology, indicating the absence of severe acute hematologic and renal toxicity. Conclusion: These results highlight that the potentiation of the therapeutic effect of PRRT by DNA-PKcs inhibition is a highly effective and well-Tolerated therapeutic strategy. Based on our findings, we recommend initiation of phase I/II studies in patients to find a safe and effective combination regimen.

Original languageEnglish
Pages (from-to)3117-3130
Number of pages14
JournalTheranostics
Volume13
Issue number10
DOIs
Publication statusPublished - 21 May 2023

Bibliographical note

Acknowledgments:
The authors thank Prof. Ola Nilsson (Sahlgren-ska Cancer Center, University of Gothenburg, Sweden) for providing the GOT1 cell line and Dr. Joerg Schrader (Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany) for providing the BON1 cell line. Additionally, the authors would like to thank the Department of Pathology at Erasmus MC Rotterdam for performing the PAS stainings on mouse kidney tissues. Fluorescent confocal imaging was performed in collaboration with the Optical Imaging Center core facility of the Erasmus MC. Animal experimentation was performed in collaboration with the Experimental Laboratory Animal Science Center of the Erasmus MC. Preparation of 177Lu-DOTA-TATE for in vitro studies was performed by the Department of Radiology and Nuclear Medicine of the Erasmus MC. This study was financed by grant number 11840 of the Dutch Cancer Society (KWF).

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