Editorial
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Oncol. Dec 10, 2015; 6(6): 194-197
Published online Dec 10, 2015. doi: 10.5306/wjco.v6.i6.194
Neuroendocrine tumors resistant to mammalian target of rapamycin inhibitors: A difficult conversion from biology to the clinic
Nicola Fazio
Nicola Fazio, Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, 20141 Milan, Italy
Author contributions: Fazio N conceived the issue which formed the content of the manuscript and wrote the manuscript.
Conflict-of-interest statement: Nicola Fazio has received fees for serving as an advisory board member for Novartis, Ipsen and Lexicon.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Nicola Fazio, MD, PhD, Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, Via Ripamonti, 43, 20141 Milan, Italy. nicola.fazio@ieo.it
Telephone: +39-02-57489258 Fax: +39-02-94379224
Received: June 29, 2015
Peer-review started: July 3, 2015
First decision: July 30, 2015
Revised: September 7, 2015
Accepted: September 25, 2015
Article in press: September 28, 2015
Published online: December 10, 2015
Processing time: 163 Days and 6 Hours
Core Tip

Core tip: Although everolimus significantly prolongs progression-free survival in patients with advanced pancreatic neuroendocrine tumors (NETs), some patients are refractory or progress early after an initial response. Mammalian target of rapamycin (mTOR) C2 and insulin growth factor (IGF) - IGF receptor signaling can mediate two supposed mechanisms of resistance to everolimus. BEZ235 is a multitargeted inhibitor binding to phosphoinositide 3-kinase, mTORC1 and mTORC2, therefore potentially turning off all the supposed molecular targets of resistance to everolimus. The two clinical trials designed in pancreatic NETs were stopped early due to unmet statistical endpoint and the global clinical development of BEZ235 was halted. Challenging tolerability probably conditioned the results. The BEZ experience is an example of the huge difference between preclinical and clinical setting and prompts us to pay more attention to the phase I step of clinical development and the design of higher-phase trials.