2. Academic Validation
  3. Inhibition of Ribonucleotide Reductase Subunit M2 Enhances the Radiosensitivity of Metastatic Pancreatic Neuroendocrine Tumor

Inhibition of Ribonucleotide Reductase Subunit M2 Enhances the Radiosensitivity of Metastatic Pancreatic Neuroendocrine Tumor

  • Cancer Lett. 2024 May 25:216993. doi: 10.1016/j.canlet.2024.216993.
Zeta Chow 1,  Jeremy Johnson 2,  Aman Chauhan 3,  Jong Cheol Jeong 4,  Jennifer T Castle 5,  Tadahide Izumi 6,  Heidi Weiss 7,  Courtney M Townsend Jr 8,  Jörg Schrader 9,  Lowell Anthony 10,  Eddy S Yang 1,  B Mark Evers 5,  Piotr Rychahou 11
Affiliations

Affiliations

  • 1 Markey Cancer Center, Lexington, KY; Department of Radiation Medicine, University of Kentucky, Lexington, KY.
  • 2 Markey Cancer Center, Lexington, KY.
  • 3 Division of Medical Oncology, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL.
  • 4 Markey Cancer Center, Lexington, KY; Department of Internal Medicine, Division of Biomedical Informatics, University of Kentucky, Lexington, KY.
  • 5 Markey Cancer Center, Lexington, KY; Department of Surgery, University of Kentucky, Lexington, KY.
  • 6 Markey Cancer Center, Lexington, KY; Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY.
  • 7 Markey Cancer Center, Lexington, KY; Department of Internal Medicine, Division of Cancer Biostatistics, University of Kentucky, Lexington KY.
  • 8 Department of Surgery, University of Texas Medical Branch, Galveston, TX.
  • 9 I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • 10 Markey Cancer Center, Lexington, KY; Department of Internal Medicine, Division of Medical Oncology, University of Kentucky, Lexington, KY.
  • 11 Markey Cancer Center, Lexington, KY; Department of Surgery, University of Kentucky, Lexington, KY. Electronic address: piotr.rychahou@uky.edu.
PMID: 38801884 DOI: 10.1016/j.canlet.2024.216993
Abstract

Ribonucleotide Reductase (RNR) is a rate-limiting Enzyme in the production of deoxyribonucleoside triphosphates (dNTPs), which are essential substrates for DNA repair after radiation damage. We explored the radiosensitization property of RNR and investigated a selective RRM2 inhibitor, 3-AP, as a radiosensitizer in the treatment of metastatic pNETs. We investigated the role of RNR subunit, RRM2, in pancreatic neuroendocrine (pNET) cells and responses to radiation in vitro. We also evaluated the selective RRM2 subunit inhibitor, 3-AP, as a radiosensitizer to treat pNET metastases in vivo. Knockdown of RNR subunits demonstrated that RRM1 and RRM2 subunits, but not p53R3, play significant roles in cell proliferation. RRM2 inhibition activated DDR pathways through phosphorylation of ATM and DNA-PK protein kinases but not ATR. RRM2 inhibition also induced Chk1 and Chk2 phosphorylation, resulting in G1/S phase cell cycle arrest. RRM2 inhibition sensitized pNET cells to radiotherapy and induced Apoptosis in vitro. In vivo, we utilized pNET subcutaneous and lung metastasis models to examine the rationale for RNR-targeted therapy and 3-AP as a radiosensitizer in treating pNETs. Combination treatment significantly increased Apoptosis of BON (human pNET) xenografts and significantly reduced the burden of lung metastases. Together, our results demonstrate that selective RRM2 inhibition induced radiosensitivity of metastatic pNETs both in vitro and in vivo. Therefore, treatment with the selective RRM2 inhibitor, 3-AP, is a promising radiosensitizer in the therapeutic armamentarium for metastatic pNETs.

Keywords

metastases; pancreatic neuroendocrine tumor; radiosensitization; radiotherapy; ribonucleotide reductase inhibitor.

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