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}
  1. Figure 1

    Effects of Everolimus and IGF1 on P-NET primary cultures. P-NET primary cultures were incubated in 96-well plates for 48 h in a culture medium supplemented with 100 nM Everolimus with (black bars) or without 100 nM IGF1 (white bars); control cells were treated with a vehicle solution. Cell viability and caspase activation of each primary culture were measured as a luminescent signal. According to the response to Everolimus in terms of cell viability inhibition, the samples were divided into ‘responder’ (6 samples) (A) and ‘non-responder’ (14 samples) (B). Data from P-NET primary cultures were evaluated independently with six replicates each, and expressed as the mean value ± s.e.m. percent cell viability inhibition vs untreated control cells (upper panels) or as the mean value ± s.e.m. percent caspase activation vs untreated control cells (lower panels). *P < 0.05 and ***P < 0.001 vs untreated control cells. #P < 0.05 and ###P < 0.001 vs cells treated with Everolimus alone.

  2. Figure 2

    IGF1/mTOR signaling pathway expression in P-NET tissues. Total proteins were isolated from 20 P-NET tissues and AlphaScreen analysis for p-IGF1 R (A), p-AKT (B), p-mTOR (C) and p-4EBP1 (D) expression in the pooled P-NET R and in the pooled P-NET NR tissues was performed, as described in the ‘Materials and methods’ section. Values are expressed after normalization against glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as AlphaScreen signal (counts). **P < 0.02 and ***P < 0.001 vs P-NET R.

  3. Figure 3

    Patients clinical characteristics and Everolimus responsiveness in vitro. (A) Median values and range of Ki67 labelling index in P-NET-R and in P-NET-NR. *P < 0.05% vs P-NET-R. (B) % P-NET-R tissues according to tumor grade. G1 P-NET-R = 1/7; G2 P-NET-R = 2/7; G3 P-NET-R = 2/2.

  4. Figure 4

    Association between p-AKT expression and clinical outcomes. (A) Immunohistochemical expression of p-AKT in a non-functioning G3 P-NET (T3N1M1), sensitive to Everolimus after surgery, defined as P-NET-R in vitro. (B) Immunohistochemical expression of p-AKT in a non-functioning G2 P-NET (T3N1M1), resistant to Everolimus after surgery and defined as P-NET-NR in vitro.

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