Neuroendocrine tumors resistant to mammalian target of rapamycin inhibitors: A difficult conversion from biology to the clinic

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.