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

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.

Metabolic Interventions in Tumor Immunity: Focus on Dual Pathway Inhibitors

“…Treatment of NET cell lines (QGP-1 and BON) with PF-04691502 downregulated the expression of pAKT for up to 72 h than in the control group. Surprisingly, concurrent treatment with PF-04691502 and radiotherapy did not enhance apoptosis in NET cells, while adding PF-04691502 48 h upon radiotherapy considerably induced apoptosis compared to radiotherapy or PF-04691502 therapy alone [ 129 ]. These outcomes indicate that combining radiation and PF-04691502 could be a novel and potential therapeutic approach for treating NETs [ 153 ].…”

Development of Clioquinol Platinum(IV) Conjugates as Autophagy-Targeted Antimetastatic Agents

“…Autophagy is a highly conserved self-degradative process that plays a critical role in cell homeostasis; meanwhile, drug-induced autophagy has long been categorized as an alternative cell death mechanism, termed as type II programmed cell death. , Recent work emphasized that autophagy was a “double-edged sword” in tumor metastasis: − it participates in the development of tumors and protects cancer cells from chemotherapeutics, but specific autophagy induced by drugs would activate apoptosis signaling pathways, facilitate multidrug resistance reversal, activate tumor immunity, and suppress metastasis. Phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway has been well-established as a critical regulator of autophagy, which was also crucial in suppressing T-cell activation and promoting immune escape. , More importantly, the inhibited PI3K/AKT/mTOR pathway would effectively attenuate angiogenesis by decreasing the expression of VEGFA and further decrease the risk of cancer metastasis. , Temsirolimus and everolimus as autophagy inducers mediated by PI3K/AKT/mTOR signaling were approved by FDA for the treatment of renal cell carcinoma, and temsirolimus was approved for relapsed mantle cell lymphoma in Europe. , Therapy targeting PI3K/AKT/mTOR-mediated autophagy has become an important focus for clinical efforts to prevent tumor growth and metastasis. − …”

“…9,10 More importantly, the inhibited PI3K/ AKT/mTOR pathway would effectively attenuate angiogenesis by decreasing the expression of VEGFA and further decrease the risk of cancer metastasis. 11,12 Temsirolimus and everolimus as autophagy inducers mediated by PI3K/AKT/mTOR signaling were approved by FDA for the treatment of renal cell carcinoma, and temsirolimus was approved for relapsed mantle cell lymphoma in Europe. 13,14 Therapy targeting PI3K/ AKT/mTOR-mediated autophagy has become an important focus for clinical efforts to prevent tumor growth and metastasis.…”

PI3K/mTOR Dual Inhibitor Pictilisib Stably Binds to Site I of Human Serum Albumin as Observed by Computer Simulation, Multispectroscopic, and Microscopic Studies

“…The phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rap (PI3K/AKT/mTOR) pathway is the most frequently and aberrantly activated pat many types of cancers and plays a key role in cancer cell growth, survival, angio and metastasis [14,15]. The PI3K/AKT/mTOR pathway has become an attractive th tic target for inhibiting the development and metastasis of tumors, resulting in th opment and ongoing clinical trials of several PI3K/AKT/mTOR inhibitors [16][17][18] inhibitors have begun to be used in clinical practice and have obtained varying de success. However, some inhibitors have limited clinical potential because of high icity, such as LY294002 [18].…”