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.
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Z.C. was supported by a National Cancer Institute training grant (T32 CA160003). C.W. and M.L.M. were supported by the National Cancer Institute “Appalachian Career Training in Oncology program” (R25 CA221765). Markey Cancer Center Shared Resource Facilities are supported by P30 CA177558. This project was supported by a generous donation from the Amanda W. Lockey Foundation.
Research data are stored in an institutional repository and will be shared upon request to the corresponding author.
The following are available online at https://www.mdpi.com/article/10.3390/cells10051261/s1, Figure S1: pAkt (Ser473) expression pNET patient tumor samples, Figure S2: pAkt (Ser473) inhibition by PKI-402 in NET cell lines at 24 h, Figure S3: Simultaneous PF-04691502 therapy and radiation therapy in NET cell lines. The materials are also available for download as the additional file listed at the end of this record.
Chow, Zeta; Johnson, Jeremy; Chauhan, Aman; Izumi, Tadahide; Cavnar, Michael; Weiss, Heidi L.; Townsend, Courtney M. Jr.; Anthony, Lowell B.; Wasilchenko, Carrigan; Melton, Matthew L.; Schrader, Jörg; Evers, B. Mark; and Rychahou, Piotr G., "PI3K/mTOR Dual Inhibitor PF-04691502 Is a Schedule-Dependent Radiosensitizer for Gastroenteropancreatic Neuroendocrine Tumors" (2021). Markey Cancer Center Faculty Publications. 164.