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Endocrine Abstracts (2016) 41 EP591 | DOI: 10.1530/endoabs.41.EP591


1Department of Medical Science, Section of Endocrinology & Internal Medicine, University of Ferrara, Ferrara, Italy; 2Pancreatic Surgery Unit, San Raffaele Hospital, Vita-Salute San Raffaele University, Milan, Italy; 3Department of Biomedical Sciences and Public Health, Polytechnic University of Marche, Ancona, Italy; 4Institut Fur Pathologie, University of Bern, Bern, Switzerland.

Introduction: Medical therapy of Pancreatic neuroendocrine tumors (P-NETs) may take advantage from mammalian target of rapamycin (mTOR) inhibitors. However, so far, the extent of therapeutic response cannot be predicted.

Aim: To investigate the possible predictors of sensitivity to mTOR inhibitors in P-NETs.

Materials and methods: P-NET primary cultures were treated with IGF1 and/or Everolimus. Cell viability and caspase activity were evaluated. Protein profiling for PI3K/AKT/mTOR pathway components was assessed by alpha screen. Validation by Tissue microarray and immunohistochemistry (IHC) was performed on 11 P-NETs. Molecular and clinico-pathological characteristics of the patients were collected.

Results: Everolimus significantly reduced cell viability and induced apoptosis up to 30% (Responder; P-NET-R) in 6 P-NETs, where the proliferative and antiapoptotic effects IGF-1 were blocked by Everolimus. On the contrary, 14 P-NETs were resistant to Everolimus and IGF-1 treatments (Non Responder; pNET-NR). Furthermore, we found that phosphorylated IGF1R, AKT, mTOR and 4EBP1 protein levels were >2 fold higher in P-NET-R as compared to P-NET-NR. Among the 11 P-NETs analysed by IHC, 2/3 P-NET-R tissues were positive for p-AKT and p-mTOR, On the contrary, 6/8 P-NET-NR tissues were negative for p-mTOR independently of the phosphorylation state of p-AKT, confirming alpha screen data. Furthermore, clinical characteristics associated with responsiveness to Everolimus in vitro were higher ki67 (≥10%) and higher grade (G3).

Conclusions: The lack of response to mTOR inhibitors associates with an inactive mTOR protein, suggesting that mTOR phosphorylation status assessed by IHC may represent a predictive marker of responsiveness to mTOR inhibitors. However, further studies are needed to confirm these data.

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