2. Academic Validation
  3. PI3K/mTOR Dual Inhibitor PF-04691502 Is a Schedule-Dependent Radiosensitizer for Gastroenteropancreatic Neuroendocrine Tumors

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

  • Cells. 2021 May 20;10(5):1261. doi: 10.3390/cells10051261.
Zeta Chow 1 2,  Jeremy Johnson 1,  Aman Chauhan 1 3,  Tadahide Izumi 1 4,  Michael Cavnar 1 2,  Heidi Weiss 1 5,  Courtney M Townsend Jr 6,  Lowell Anthony 1 3,  Carrigan Wasilchenko 1,  Matthew L Melton 1,  Jörg Schrader 7,  B Mark Evers 1 2,  Piotr Rychahou 1 2
Affiliations

Affiliations

  • 1 Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA.
  • 2 Department of Surgery, University of Kentucky, Lexington, KY 40536, USA.
  • 3 Department of Internal Medicine, Division of Medical Oncology, University of Kentucky, Lexington, KY 40536, USA.
  • 4 Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40536, USA.
  • 5 Department of Internal Medicine, Division of Cancer Biostatistics, University of Kentucky, Lexington, KY 40536, USA.
  • 6 Department of Surgery, University of Texas Medical Branch, Galveston, TX 77555, USA.
  • 7 Medical Department and Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.
PMID: 34065268 DOI: 10.3390/cells10051261
Abstract

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.

Keywords

PI3K inhibitor; neuroendocrine tumor; radiosensitization.

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