mTOR inhibitors response and mTOR pathway in pancreatic neuroendocrine tumors

    1. Maria Chiara Zatelli1
    1. 1Department of Medical Science, Section of Endocrinology and Internal Medicine, University of Ferrara, Ferrara, Italy
    2. 2Pancreatic Surgery Unit, Pancreas Translational and Research Institute, San Raffaele Hospital, Vita-Salute San Raffaele University, Milan, Italy
    3. 3Department of Biomedical Sciences and Public Health, Polytechnic University of Marche, Ancona, Italy
    4. 4Institut fur Pathologie, University of Bern, Bern, Switzerland
    1. Correspondence should be addressed to M C Zatelli; Email: ztlmch{at}


    Medical therapy of pancreatic neuroendocrine tumors (P-NET) may take advantage of Everolimus treatment. However, the extent of therapeutic response cannot be predicted. This study was aimed to identify the possible predictive markers of response to Everolimus in P-NET. We found that Everolimus reduced the cell viability and induced apoptosis in primary cultures of 6 P-NET (P-NET-R), where the proliferative and antiapoptotic effects of IGF1 were blocked by Everolimus. On the contrary, 14 P-NET primary cultures (P-NET-NR) were resistant to Everolimus and IGF1, suggesting an involvement of PI3K/AKT/mTOR pathway in the mechanism of resistance. The response to Everolimus in vitro was associated with an active AKT/mTOR pathway and seemed to be associated with a greater clinical aggressiveness. In addition, a patient sensitive to Everolimus in vitro was sensitive to this drug in vivo also and showed a positive p-AKT immunohistochemistry (IHC) at tissue level. Similarly, a patient resistant to Everolimus treatment after surgery was not sensitive to the drug in vitro and had a negative p-AKT IHC staining. Therefore, present data confirm that P-NET primary cultures may be considered a model for testing medical treatment efficacy and that IHC characterization of p-AKT might help in identifying human P-NET who can benefit from Everolimus treatment. These data encourage conducting a prospective multicenter study involving different groups of P-NET patients treated with Everolimus.

    • Received 21 September 2016
    • Accepted 3 October 2016
    • Made available online as an Accepted Preprint 3 October 2016
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