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Theranostics 2023; 13(10):3117-3130. doi:10.7150/thno.82963 This issue Cite

Research Paper

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

Thom G.A. Reuvers1,2, Nicole S. Verkaik1, Debra Stuurman2,3, Corrina de Ridder3, Marian C. Clahsen-van Groningen4,5, Erik de Blois2, Julie Nonnekens1,2,✉

1. Department of Molecular Genetics, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, The Netherlands.
2. Department of Radiology and Nuclear Medicine, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, The Netherlands.
3. Department of Urology, Erasmus University Medical Center Rotterdam, The Netherlands.
4. Department of Pathology, Erasmus University Medical Center Rotterdam, The Netherlands.
5. Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany.

✉ Corresponding author: Dr. Julie Nonnekens, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015GD, Rotterdam. E-mail: j.nonnekensnl.

Citation:
Reuvers TGA, Verkaik NS, Stuurman D, de Ridder C, Groningen MCCv, de Blois E, Nonnekens J. DNA-PKcs inhibitors sensitize neuroendocrine tumor cells to peptide receptor radionuclide therapy in vitro and in vivo. Theranostics 2023; 13(10):3117-3130. doi:10.7150/thno.82963. https://www.thno.org/v13p3117.htm
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Abstract

Graphic 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.

Keywords: Neuroendocrine tumors, peptide receptor radionuclide therapy, DDR inhibitors, DNA-PKcs, ionizing radiation

Citation styles

APA
Reuvers, T.G.A., Verkaik, N.S., Stuurman, D., de Ridder, C., Groningen, M.C.C.v., de Blois, E., Nonnekens, J. (2023). DNA-PKcs inhibitors sensitize neuroendocrine tumor cells to peptide receptor radionuclide therapy in vitro and in vivo. Theranostics, 13(10), 3117-3130. https://doi.org/10.7150/thno.82963.

ACS
Reuvers, T.G.A.; Verkaik, N.S.; Stuurman, D.; de Ridder, C.; Groningen, M.C.C.v.; de Blois, E.; Nonnekens, J. DNA-PKcs inhibitors sensitize neuroendocrine tumor cells to peptide receptor radionuclide therapy in vitro and in vivo. Theranostics 2023, 13 (10), 3117-3130. DOI: 10.7150/thno.82963.

NLM
Reuvers TGA, Verkaik NS, Stuurman D, de Ridder C, Groningen MCCv, de Blois E, Nonnekens J. DNA-PKcs inhibitors sensitize neuroendocrine tumor cells to peptide receptor radionuclide therapy in vitro and in vivo. Theranostics 2023; 13(10):3117-3130. doi:10.7150/thno.82963. https://www.thno.org/v13p3117.htm

CSE
Reuvers TGA, Verkaik NS, Stuurman D, de Ridder C, Groningen MCCv, de Blois E, Nonnekens J. 2023. DNA-PKcs inhibitors sensitize neuroendocrine tumor cells to peptide receptor radionuclide therapy in vitro and in vivo. Theranostics. 13(10):3117-3130.

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