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Endocr Relat Cancer. 2016 Nov;23(11):883-891. Epub 2016 Oct 3.

mTOR inhibitors response and mTOR pathway in pancreatic neuroendocrine tumors.

Author information

1
Department of Medical ScienceSection of Endocrinology and Internal Medicine, University of Ferrara, Ferrara, Italy.
2
Pancreatic Surgery UnitPancreas Translational and Research Institute, San Raffaele Hospital, Vita-Salute San Raffaele University, Milan, Italy.
3
Department of Biomedical Sciences and Public HealthPolytechnic University of Marche, Ancona, Italy.
4
Institut fur PathologieUniversity of Bern, Bern, Switzerland.
5
Department of Medical ScienceSection of Endocrinology and Internal Medicine, University of Ferrara, Ferrara, Italy ztlmch@unife.it.

Abstract

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.

KEYWORDS:

Everolimus; IGF1; pancreatic neuroendocrine tumors; predictive markers; primary cultures

PMID:
27697900
DOI:
10.1530/ERC-16-0329
[Indexed for MEDLINE]

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