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PI3K/mTOR Dual Inhibitor PF-04691502 Is a Schedule-Dependent Radiosensitizer for Gastroenteropancreatic Neuroendocrine Tumors

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Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA
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Department of Surgery, University of Kentucky, Lexington, KY 40536, USA
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Department of Internal Medicine, Division of Medical Oncology, University of Kentucky, Lexington, KY 40536, USA
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Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40536, USA
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Department of Internal Medicine, Division of Cancer Biostatistics, University of Kentucky, Lexington, KY 40536, USA
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Department of Surgery, University of Texas Medical Branch, Galveston, TX 77555, USA
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Medical Department and Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
*
Author to whom correspondence should be addressed.
Academic Editor: Alexander E. Kalyuzhny
Cells 2021, 10(5), 1261; https://doi.org/10.3390/cells10051261
Received: 24 February 2021 / Revised: 12 May 2021 / Accepted: 14 May 2021 / Published: 20 May 2021
Patients with advanced-stage gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have a poor overall prognosis despite chemotherapy and radiotherapy (e.g., peptide receptor radionuclide therapy (PRRT)). Better treatment options are needed to improve disease regression and patient survival. The purpose of this study was to examine a new treatment strategy by combining PI3K/mTOR dual inhibition and radiotherapy. First, we assessed the efficacy of two PI3K/mTOR dual inhibitors, PF-04691502 and PKI-402, to inhibit pAkt and increase apoptosis in NET cell lines (BON and QGP-1) and patient-derived tumor spheroids as single agents or combined with radiotherapy (XRT). Treatment with PF-04691502 decreased pAkt (Ser473) expression for up to 72 h compared with the control; in contrast, decreased pAkt expression was noted for less than 24 h with PKI-402. Simultaneous treatment with PF-04691502 and XRT did not induce apoptosis in NET cells; however, the addition of PF-04691502 48 h after XRT significantly increased apoptosis compared to PF-04691502 or XRT treatment alone. Our results demonstrate that schedule-dependent administration of a PI3K/mTOR inhibitor, combined with XRT, can enhance cytotoxicity by promoting the radiosensitivity of NET cells. Moreover, our findings suggest that radiotherapy, in combination with timed PI3K/mTOR inhibition, may be a promising therapeutic regimen for patients with GEP-NET. View Full-Text
Keywords: neuroendocrine tumor; radiosensitization; PI3K inhibitor neuroendocrine tumor; radiosensitization; PI3K inhibitor
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MDPI and ACS Style

Chow, Z.; Johnson, J.; Chauhan, A.; Izumi, T.; Cavnar, M.; Weiss, H.; Townsend, C.M., Jr.; Anthony, L.; Wasilchenko, C.; Melton, M.L.; Schrader, J.; Evers, B.M.; Rychahou, P. PI3K/mTOR Dual Inhibitor PF-04691502 Is a Schedule-Dependent Radiosensitizer for Gastroenteropancreatic Neuroendocrine Tumors. Cells 2021, 10, 1261. https://doi.org/10.3390/cells10051261

AMA Style

Chow Z, Johnson J, Chauhan A, Izumi T, Cavnar M, Weiss H, Townsend CM Jr., Anthony L, Wasilchenko C, Melton ML, Schrader J, Evers BM, Rychahou P. PI3K/mTOR Dual Inhibitor PF-04691502 Is a Schedule-Dependent Radiosensitizer for Gastroenteropancreatic Neuroendocrine Tumors. Cells. 2021; 10(5):1261. https://doi.org/10.3390/cells10051261

Chicago/Turabian Style

Chow, Zeta, Jeremy Johnson, Aman Chauhan, Tadahide Izumi, Michael Cavnar, Heidi Weiss, Courtney M. Townsend Jr., Lowell Anthony, Carrigan Wasilchenko, Matthew L. Melton, Jörg Schrader, B. M. Evers, and Piotr Rychahou. 2021. "PI3K/mTOR Dual Inhibitor PF-04691502 Is a Schedule-Dependent Radiosensitizer for Gastroenteropancreatic Neuroendocrine Tumors" Cells 10, no. 5: 1261. https://doi.org/10.3390/cells10051261

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