title: Combined therapy with RAD001 e BEZ235 overcomes resistance of PET immortalized cell lines to mTOR inhibition.
abstract: Pancreatic endocrine tumors (PETs) are characterised by an indolent behaviour in terms of tumor growth. However, most patients display metastasis at diagnosis and no cure is currently available. Since the PI3K/AKT/mTOR axis is deregulated in PETs, the mTOR inhibitor RAD001 represents the first line treatment. Nevertheless, some patients do not respond to treatments and most acquire resistance. Inhibition of mTOR leads to feedback re-activation of PI3K activity, which may promote resistance to RAD001. Thus, PI3K represents a novel potential target for PETs. We tested the impact of three novel PI3K inhibitors (BEZ235, BKM120 and BYL719) on proliferation of PET cells that are responsive (BON-1) or unresponsive (QGP-1) to RAD001. BEZ235 was the most efficient in inhibiting proliferation in PET cells. Furthermore, combined treatment with BEZ235 and RAD001 exhibited synergic effects and was also effective in BON-1 that acquired resistance to RAD001 (BON-1 RR). Analysis of PI3K/AKT/mTOR pathway showed that RAD001 and BEZ235 only partially inhibited mTOR-dependent phosphorylation of 4EBP1. By contrast, combined therapy with the two inhibitors strongly inhibited phosphorylation of 4EBP1, assembly of the translational initiation complex and protein synthesis. Thus, combined treatment with BEZ235 may represent suitable therapy to counteract primary and acquired resistance to RAD001 in PETs.
authors.affiliation: Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy; Digestive & Liver Disease Unit, University of La Sapienza, Rome, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Passacantilli
authors.affiliation: Digestive & Liver Disease Unit, University of La Sapienza, Rome, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Capurso
authors.affiliation: Digestive & Liver Disease Unit, University of La Sapienza, Rome, Italy.
authors.forename: Livia
authors.initials: L
authors.lastname: Archibugi
authors.affiliation: Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy; Digestive & Liver Disease Unit, University of La Sapienza, Rome, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Calabretta
authors.affiliation: Department of Biology, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Caldarola
authors.affiliation: Department of Biology, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Loreni
authors.affiliation: Digestive & Liver Disease Unit, University of La Sapienza, Rome, Italy.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Delle Fave
authors.affiliation: Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy; Laboratory of Neuroembryology, Fondazione Santa Lucia, Rome, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Sette
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000068338:Everolimus; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D018358:Neuroendocrine Tumors / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D010766:Phosphorylation; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D007093:Imidazoles; D011804:Quinolines; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; C531198:dactolisib; D020123:Sirolimus