Combined therapy with RAD001 e BEZ235 overcomes resistance of PET immortalized cell lines to mTOR inhibition

// Ilaria Passacantilli 1,2 , Gabriele Capurso 2 , Livia Archibugi 2 , Sara Calabretta 1,2 , Sara Caldarola 3 , Fabrizio Loreni 3 , Gianfranco Delle Fave 2 and Claudio Sette 1,4 1 Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy 2 Digestive & Liver Disease Unit, University of La Sapienza, Rome, Italy 3 Department of Biology, University of Rome Tor Vergata, Rome, Italy 4 Laboratory of Neuroembryology, Fondazione Santa Lucia, Rome, Italy Correspondence: Claudio Sette, email: // Gianfranco Delle Fave, email: // Keywords : PETs; mTORC1 chemical inhibitors; RAD001; BEZ235; adaptation to chronic treatment; combined treatment Received : March 28, 2014 Accepted : June 17, 2014 Published : June 18, 2014 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.