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.
authors.affiliation: Department of Medical ScienceSection of Endocrinology and Internal Medicine, University of Ferrara, Ferrara, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Falletta
authors.affiliation: Pancreatic Surgery UnitPancreas Translational and Research Institute, San Raffaele Hospital, Vita-Salute San Raffaele University, Milan, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Partelli
authors.affiliation: Department of Biomedical Sciences and Public HealthPolytechnic University of Marche, Ancona, Italy.
authors.forename: Corrado
authors.initials: C
authors.lastname: Rubini
authors.affiliation: Institut fur PathologieUniversity of Bern, Bern, Switzerland.
authors.forename: Dominik
authors.initials: D
authors.lastname: Nann
authors.affiliation: Department of Biomedical Sciences and Public HealthPolytechnic University of Marche, Ancona, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Doria
authors.affiliation: Institut fur PathologieUniversity of Bern, Bern, Switzerland.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Marinoni
authors.affiliation: Pancreatic Surgery UnitPancreas Translational and Research Institute, San Raffaele Hospital, Vita-Salute San Raffaele University, Milan, Italy.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Polenta
authors.affiliation: Department of Medical ScienceSection of Endocrinology and Internal Medicine, University of Ferrara, Ferrara, Italy.
authors.forename: Carmelina
authors.initials: C
authors.lastname: Di Pasquale
authors.affiliation: Department of Medical ScienceSection of Endocrinology and Internal Medicine, University of Ferrara, Ferrara, Italy.
authors.forename: Ettore
authors.initials: E
authors.lastname: Degli Uberti
authors.affiliation: Institut fur PathologieUniversity of Bern, Bern, Switzerland.
authors.forename: Aurel
authors.initials: A
authors.lastname: Perren
authors.affiliation: Pancreatic Surgery UnitPancreas Translational and Research Institute, San Raffaele Hospital, Vita-Salute San Raffaele University, Milan, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Falconi
authors.affiliation: Department of Medical ScienceSection of Endocrinology and Internal Medicine, University of Ferrara, Ferrara, Italy ztlmch@unife.it.
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Zatelli
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D000068338:Everolimus / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D061251:Primary Cell Culture; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Everolimus; IGF1; pancreatic neuroendocrine tumors; predictive markers; primary cultures