MTOR inhibitors response and mTOR pathway in pancreatic neuroendocrine tumors. Issue 11 (November 2016)

• Record Type: Journal Article
• Authors: Falletta, Simona; Partelli, Stefano; Rubini, Corrado; Nann, Dominik; Doria, Andrea; Marinoni, Ilaria; Polenta, Vanessa; Di Pasquale, Carmelina; degli Uberti, Ettore; Perren, Aurel; Falconi, Massimo; Zatelli, Maria Chiara
• Is Part Of: Endocrine-related cancer. Volume 23:Issue 11(2016)
• Page Start: 883
• Page End: 891
• Publication Date: 2016-11
• Subjects: pancreatic neuroendocrine tumors -- Everolimus -- IGF1 -- primary cultures -- predictive markers; Endocrine glands -- Cancer -- Periodicals; Endocrinology -- Periodicals; Cancer -- Endocrine aspects -- Periodicals; 616.9944005
• DOI: 10.1530/ERC-16-0329
• Languages: English
• ISSNs: 1351-0088

Abstract

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.