Cotargeting the PI3K and RAS Pathways for the Treatment of Neuroendocrine Tumors

Abstract

Background The precise involvement of the PI3K/mTOR and RAS/MEK pathways in carcinoid tumors is not well defined. Therefore, the purpose of our study was to evaluate the role these pathways play in carcinoid cell proliferation, apoptosis, and secretion and to determine the effects of combined treatment on carcinoid tumor inhibition. Methods The human neuroendocrine cell lines BON (pancreatic carcinoid), NCI-H727 (lung carcinoid), and QGP-1 (somatostatinoma) were treated with either the pan-PI3K inhibitor, BKM120, or the dual PI3K-mTOR inhibitor, BEZ235, alone or in combination with the MEK inhibitor, PD0325901; proliferation, apoptosis, and protein expression were assessed. Peptide secretion was evaluated in BON and QGP-1 cells. The anti-proliferative effect of BEZ235, alone or combined with PD0325901, was then tested in vivo. Results Both BKM120 and BEZ235 decreased proliferation and increased apoptosis; combination with PD0325901 significantly enhanced the antineoplastic effects of either treatment alone. In contrast, neurotensin (NT) peptide secretion was markedly stimulated with BKM120 treatment, but not BEZ235. The combination of BEZ235 + PD0325901 significantly inhibited the growth of BON xenografts without systemic toxicity. Conclusions Both BKM120 and BEZ235 effectively inhibited NET cell proliferation and stimulated apoptosis. However, inhibition of the PI3K pathway alone with BKM120 significantly stimulated NT peptide secretion; this did not occur with the dual inhibition of both PI3K and mTOR using BEZ235 suggesting that this would be a more effective treatment regimen for NETs. Moreover, the combination of BEZ235 and the MEK inhibitor PD0325901 was a safe and more effective therapy in vivo compared with single agents alone.

Rapamycin Prolongs Cardiac Allograft Survival in a Mouse Model by Inducing Myeloid-Derived Suppressor Cells

“…Interestingly, there appears to be a consensus regarding activation of Janus kinase protein and STAT 3 and 5 (47). Indeed, some reports argue that STAT 3 and 5 regulate MDSC function in both mice and humans (9,10,48 (20). Thus, these findings appear to be important in terms of MDSC induction by mTOR inhibitors or other immunosuppressive drugs in the context of clinical organ transplantation.…”

“…Interestingly, studies show that inhibiting mTOR activates the Raf/mitogen-activated protein kinase kinase (MEK)/ extracellular signal regulated kinase (ERK) pathway (17)(18)(19). Indeed, dual inhibition of the mTOR and Raf/MEK/ERK signaling pathways is an attractive therapy for malignant tumors (20,21).…”

The neuroendocrine phenotype, genomic profile and therapeutic sensitivity of GEPNET cell lines

“…Among the most frequently used PanNET cell lines are QGP-1 and BON-1. QGP-1 was established in 1980 from a somatostatin-producing islet cell carcinoma (Kaku et al 1980, Iguchi et al 1990 and it has been used to study the molecular mechanisms that regulate tumour cell proliferation (Doihara et al 2009, Valentino et al 2014. BON-1 was established in 1991 from a lymph node metastasis of a PanNET patient (Evers et al 1991) and has been used as a model for studying the molecular mechanisms of PanNETs and their sensitivity to therapy.…”

GSK3α/β: A Novel Therapeutic Target for Neuroendocrine Tumors

“…This potential escape mechanism of the cell may be due to a similar mechanism as caused by the mTORC1-inhibitor everolimus that also leads to compensatory Akt and ERK activation [56][57][58][59][60]. Compensatory feedback loops of PI3K/Akt/mTORC1 and Ras/Raf/ MEK/ERK signaling are well described in NET cells [17,[61][62][63]. Therefore, we tested a combination treatment with the HMG-CoA reductase inhibitor, lovastatin, which is known to inhibit Akt and ERK signaling and has demonstrated antitumor potential in many cancer types including NETs in vitro [38,39,64,65].…”