Key Points
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TOR (target of rapamycin) is a Ser/Thr kinase that is present in all eukaryotes. It integrates various stresses and various inputs that are indicative of cellular energy and nutrient status, and then signals to control cellular growth, translation, metabolism and survival. TOR forms two structurally and functionally distinct complexes — the rapamycin-sensitive TOR complex 1 (TORC1) and the rapamycin-insensitive TORC2 — each of which regulates different cellular responses.
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Many components within the mammalian TOR (mTOR) signalling network are tumour suppressors or oncogenes, and TOR signalling is frequently dysregulated in cancer. mTOR also plays an important part in the control of whole-body metabolism, and its overactivation by excessive nutrient intake is implicated in the development of diabetes. Pharmacological downregulation of TOR signalling has also been shown to mimic the effects of dietary restriction to prolong lifespan in yeast, worms, flies and mice.
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Rapamycin and its derivatives (collectively known as rapalogues) have been clinically approved for some cancer indications. They bind TOR allosterically in complex with FK506-binding protein 12 (FKBP12) to inhibit TORC1 activity. Nevertheless, the absence of broad clinical effectiveness is surprising given the central role of TOR signalling, and suggests that the full therapeutic potential of TOR inhibition is not being exploited.
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This has spurred the development of ATP-competitive inhibitors of TOR kinase activity. These compounds hold the promise of providing more comprehensive and sustained TORC1 inhibition than rapamycin, in addition to inhibition of TORC2 activity.
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Owing to TOR's similarity to phosphoinositide 3-kinase (PI3K), many ATP-competitive TOR inhibitors also target PI3K activity. This allows classification into: dual mTOR/PI3K inhibitors (both kinases inhibited at similar effective concentrations) and pan-mTOR inhibitors (greater selectivity for mTOR over PI3K).
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The ATP-competitive TOR inhibitors are generally superior to rapamycin in inhibiting tumour proliferation in preclinical models, and several are in Phase I clinical trials. Nevertheless, there are concerns as to their toxicity and eventual clinical efficacy.
Abstract
Mammalian target of rapamycin (mTOR) is an atypical protein kinase that controls growth and metabolism in response to nutrients, growth factors and cellular energy levels, and it is frequently dysregulated in cancer and metabolic disorders. Rapamycin is an allosteric inhibitor of mTOR, and was approved as an immuno-suppressant in 1999. In recent years, interest has focused on its potential as an anticancer drug. However, the performance of rapamycin and its analogues (rapalogues) has been undistinguished despite isolated successes in subsets of cancer, suggesting that the full therapeutic potential of targeting mTOR has yet to be exploited. A new generation of ATP-competitive inhibitors that directly target the mTOR catalytic site display potent and comprehensive mTOR inhibition and are in early clinical trials.
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We acknowledge support from the Canton of Basel, the Louis-Jeantet Foundation and the Swiss National Science Foundation.
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Benjamin, D., Colombi, M., Moroni, C. et al. Rapamycin passes the torch: a new generation of mTOR inhibitors. Nat Rev Drug Discov 10, 868–880 (2011). https://doi.org/10.1038/nrd3531
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DOI: https://doi.org/10.1038/nrd3531
