MTOR inhibitors response and mTOR pathway in pancreatic neuroendocrine tumors

Simona Falletta, Stefano Partelli, Corrado Rubini, Dominik Nann, Andrea Doria, Ilaria Marinoni, Vanessa Polenta, Carmelina Di Pasquale, Ettore Degli Uberti, Aurel Perren, Massimo Falconi, Maria Chiara Zatelli

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)883-891
Number of pages9
JournalEndocrine-Related Cancer
Volume23
Issue number11
DOIs
Publication statusPublished - Nov 1 2016

Fingerprint

Neuroendocrine Tumors
Immunohistochemistry
Everolimus
Therapeutics
Phosphatidylinositol 3-Kinases
Pharmaceutical Preparations
Multicenter Studies
Cell Survival
Prospective Studies
Apoptosis
Staining and Labeling

Keywords

  • Everolimus
  • IGF1
  • Pancreatic neuroendocrine tumors
  • Predictive markers
  • Primary cultures

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Oncology
  • Endocrinology
  • Cancer Research

Cite this

Falletta, S., Partelli, S., Rubini, C., Nann, D., Doria, A., Marinoni, I., ... Zatelli, M. C. (2016). MTOR inhibitors response and mTOR pathway in pancreatic neuroendocrine tumors. Endocrine-Related Cancer, 23(11), 883-891. https://doi.org/10.1530/ERC-16-0329

MTOR inhibitors response and mTOR pathway in pancreatic neuroendocrine tumors. / Falletta, Simona; Partelli, Stefano; Rubini, Corrado; Nann, Dominik; Doria, Andrea; Marinoni, Ilaria; Polenta, Vanessa; Di Pasquale, Carmelina; Uberti, Ettore Degli; Perren, Aurel; Falconi, Massimo; Zatelli, Maria Chiara.

In: Endocrine-Related Cancer, Vol. 23, No. 11, 01.11.2016, p. 883-891.

Research output: Contribution to journalArticle

Falletta, S, Partelli, S, Rubini, C, Nann, D, Doria, A, Marinoni, I, Polenta, V, Di Pasquale, C, Uberti, ED, Perren, A, Falconi, M & Zatelli, MC 2016, 'MTOR inhibitors response and mTOR pathway in pancreatic neuroendocrine tumors', Endocrine-Related Cancer, vol. 23, no. 11, pp. 883-891. https://doi.org/10.1530/ERC-16-0329
Falletta S, Partelli S, Rubini C, Nann D, Doria A, Marinoni I et al. MTOR inhibitors response and mTOR pathway in pancreatic neuroendocrine tumors. Endocrine-Related Cancer. 2016 Nov 1;23(11):883-891. https://doi.org/10.1530/ERC-16-0329
Falletta, Simona ; Partelli, Stefano ; Rubini, Corrado ; Nann, Dominik ; Doria, Andrea ; Marinoni, Ilaria ; Polenta, Vanessa ; Di Pasquale, Carmelina ; Uberti, Ettore Degli ; Perren, Aurel ; Falconi, Massimo ; Zatelli, Maria Chiara. / MTOR inhibitors response and mTOR pathway in pancreatic neuroendocrine tumors. In: Endocrine-Related Cancer. 2016 ; Vol. 23, No. 11. pp. 883-891.
@article{7aae19a73a7547558e70e41acfc1b55f,
title = "MTOR inhibitors response and mTOR pathway in pancreatic neuroendocrine tumors",
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",
author = "Simona Falletta and Stefano Partelli and Corrado Rubini and Dominik Nann and Andrea Doria and Ilaria Marinoni and Vanessa Polenta and {Di Pasquale}, Carmelina and Uberti, {Ettore Degli} and Aurel Perren and Massimo Falconi and Zatelli, {Maria Chiara}",
year = "2016",
month = "11",
day = "1",
doi = "10.1530/ERC-16-0329",
language = "English",
volume = "23",
pages = "883--891",
journal = "Endocrine-Related Cancer",
issn = "1351-0088",
publisher = "BioScientifica Ltd.",
number = "11",

}

TY - JOUR

T1 - MTOR inhibitors response and mTOR pathway in pancreatic neuroendocrine tumors

AU - Falletta, Simona

AU - Partelli, Stefano

AU - Rubini, Corrado

AU - Nann, Dominik

AU - Doria, Andrea

AU - Marinoni, Ilaria

AU - Polenta, Vanessa

AU - Di Pasquale, Carmelina

AU - Uberti, Ettore Degli

AU - Perren, Aurel

AU - Falconi, Massimo

AU - Zatelli, Maria Chiara

PY - 2016/11/1

Y1 - 2016/11/1

N2 - 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.

AB - 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.

KW - Everolimus

KW - IGF1

KW - Pancreatic neuroendocrine tumors

KW - Predictive markers

KW - Primary cultures

UR - http://www.scopus.com/inward/record.url?scp=84995402608&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84995402608&partnerID=8YFLogxK

U2 - 10.1530/ERC-16-0329

DO - 10.1530/ERC-16-0329

M3 - Article

AN - SCOPUS:84995402608

VL - 23

SP - 883

EP - 891

JO - Endocrine-Related Cancer

JF - Endocrine-Related Cancer

SN - 1351-0088

IS - 11

ER -