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mTOR signaling and drug development in cancer

Nature Reviews Clinical Oncology volume 7, pages 209–219 (2010)Cite this article

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Abstract

Mammalian target of rapamycin (mTOR) is a protein kinase of the PI3K/Akt signaling pathway. Activation of mTOR in response to growth, nutrient and energy signals leads to an increase in protein synthesis, which is required for tumor development. This feature makes mTOR an attractive target for cancer therapy. First-generation mTOR inhibitors are sirolimus derivatives (rapalogs), which have been evaluated extensively in cancer patients. Everolimus and temsirolimus are already approved for the treatment of renal-cell carcinoma. Temsirolimus is also approved for the treatment of mantle-cell lymphoma. These drugs, in addition to ridaforolimus (formerly deforolimus) and sirolimus, are currently being evaluated in clinical trials of various cancers. Second-generation mTOR inhibitors are small molecules that target the kinase domain, and have also entered clinical development. Clinical trials are underway to identify additional malignancies that respond to mTOR inhibitors, either alone or in combination with other therapies. Future research should evaluate the optimal drug regimens, schedules, patient populations, and combination strategies for this novel class of agents.

Key Points

  • Mammalian target of rapamycin (mTOR) is a central regulator of cell proliferation in response to growth factors and energy stimuli

  • In some tumor types, such as renal-cell carcinoma and certain lymphomas, mTOR has a key role in tumor cell proliferation and angiogenesis

  • Temsirolimus and everolimus administered as single agents are associated with substantial improvements in patients with advanced renal-cell carcinoma, and are approved for use in this indication

  • Temsirolimus is also approved for use in mantle-cell lymphoma, where it has shown a notable improvement in progression-free survival

  • Biomarkers that assess pathway activation are being explored to identify tumor types that are sensitive to mTOR inhibition

  • Combinations of targeted therapies could improve outcomes by augmenting anti-tumor activity and overcoming mechanisms of resistance

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Figure 1: mTOR signaling pathways.
Figure 2: mTOR pathway feedback loops.

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    Janet Dancey

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Dancey, J. mTOR signaling and drug development in cancer. Nat Rev Clin Oncol 7, 209–219 (2010). https://doi.org/10.1038/nrclinonc.2010.21

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