Mechanisms of resistance to mTOR inhibitors

•PI3K/AKT/mTOR pathway is disrupted in multiple tumor types.•Several class of mTOR inhibitors exist, with different mechanisms of resistance.•It is crucial to identify factors predictive/prognostic of response/resistance.•Predictive factors may help to select patients benefiting from a specific agent.•Novel and different mechanisms of resistance are still under investigation. In several tumors the PI3K/AKT/mTOR pathway is frequently disrupted, an event that results in uncontrolled cell proliferation and tumor growth. Through the years, several compounds have been developed to inhibit the pathway at different steps: the mammalian target of rapamycin (mTOR) seemed to be the most qualified target. However, this kinase has such a key role in cell survival that mechanisms of resistance are rapidly developed. Nevertheless, clinical results obtained with mTOR inhibitors in breast cancer, renal cell carcinoma, neuroendocrine tumors and mantle cell lymphoma push oncologists to actively further develop these drugs, maybe by better selecting the population to which they are offered, through the research of predictive factors of responsiveness. In this review, we aim to describe mechanisms of resistance to mTOR inhibitors, from preclinical and clinical perspectives.