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      mTOR inhibitors in cancer therapy

      review-article
      Author(s): 1 , 1 , 2 , a , 1 , 2
      Publication date (Electronic):
      Journal: F1000Research
      Publisher: F1000Research
      Keywords: mTOR, rapamycin, mTOR inhibitors, cancer therapy

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          Abstract

          The mammalian target of rapamycin, mTOR, plays key roles in cell growth and proliferation, acting at the catalytic subunit of two protein kinase complexes: mTOR complexes 1 and 2 (mTORC1/2). mTORC1 signaling is switched on by several oncogenic signaling pathways and is accordingly hyperactive in the majority of cancers. Inhibiting mTORC1 signaling has therefore attracted great attention as an anti-cancer therapy. However, progress in using inhibitors of mTOR signaling as therapeutic agents in oncology has been limited by a number of factors, including the fact that the classic mTOR inhibitor, rapamycin, inhibits only some of the effects of mTOR; the existence of several feedback loops; and the crucial importance of mTOR in normal physiology.

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          Rapamycin: one drug, many effects.

          Jing Li, Sang Gyun Kim, John Blenis (2014)
          The mammalian target of rapamycin (mTOR) signaling pathway is a master regulator of cell growth and metabolism. Deregulation of the mTOR pathway has been implicated in a number of human diseases such as cancer, diabetes, obesity, neurological diseases, and genetic disorders. Rapamycin, a specific inhibitor of mTOR, has been shown to be useful in the treatment of certain diseases. Here we discuss its mechanism of action and highlight recent findings regarding the effects and limitations of rapamycin monotherapy and the potential utility of combination therapy with rapamycin. Copyright © 2014 Elsevier Inc. All rights reserved.
          Article 0 comments Cited 432 times – based on 0 reviews     Review now
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            Akt signalling in health and disease.

            Ingeborg Hers, Emma Vincent, Jeremy Tavaré (2011)
            Akt (also known as protein kinase B or PKB) comprises three closely related isoforms Akt1, Akt2 and Akt3 (or PKBα/β/γ respectively). We have a very good understanding of the mechanisms by which Akt isoforms are activated by growth factors and other extracellular stimuli as well as by oncogenic mutations in key upstream regulatory proteins including Ras, PI3-kinase subunits and PTEN. There are also an ever increasing number of Akt substrates being identified that play a role in the regulation of the diverse array of biological effects of activated Akt; this includes the regulation of cell proliferation, survival and metabolism. Dysregulation of Akt leads to diseases of major unmet medical need such as cancer, diabetes, cardiovascular and neurological diseases. As a result there has been substantial investment in the development of small molecular Akt inhibitors that act competitively with ATP or phospholipid binding, or allosterically. In this review we will briefly discuss our current understanding of how Akt isoforms are regulated, the substrate proteins they phosphorylate and how this integrates with the role of Akt in disease. We will furthermore discuss the types of Akt inhibitors that have been developed and are in clinical trials for human cancer, as well as speculate on potential on-target toxicities, such as disturbances of heart and vascular function, metabolism, memory and mood, which should be monitored very carefully during clinical trial. Copyright © 2011 Elsevier Inc. All rights reserved.
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              Amino acid signalling upstream of mTOR.

              Jenna L. Jewell, Ryan C Russell, Kun-Liang Guan (2013)
              Mammalian target of rapamycin (mTOR) is a conserved Ser/Thr kinase that is part of mTOR complex 1 (mTORC1), a master regulator that couples amino acid availability to cell growth and autophagy. Multiple cues modulate mTORC1 activity, such as growth factors, stress, energy status and amino acids. Although amino acids are key environmental stimuli, exactly how they are sensed and how they activate mTORC1 is not fully understood. Recently, a model has emerged whereby mTORC1 activation occurs at the lysosome and is mediated through an amino acid sensing cascade involving RAG GTPases, Ragulator and vacuolar H(+)-ATPase (v-ATPase).
              Article 0 comments Cited 323 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): F1000Res
                Journal ID (iso-abbrev): F1000Res
                Journal ID (pmc): F1000Research
                Title: F1000Research
                Publisher: F1000Research (London, UK )
                ISSN (Electronic): 2046-1402
                Publication date (Electronic): 25 August 2016
                Publication date Collection: 2016
                Volume: 5
                Electronic Location Identifier: F1000 Faculty Rev-2078
                Affiliations
                [1 ]Nutrition and Metabolism, South Australian Health and Medical research Institute, Adelaide, SA, Australia
                [2 ]School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia
                Author notes

                Competing interests: The authors declare that they have no competing interests.

                Article
                DOI: 10.12688/f1000research.9207.1
                PMC ID: 5007757
                PubMed ID: 27635236
                SO-VID: 8292a82c-2199-41f8-84e3-9210036ace42
                Copyright © Copyright: © 2016 Xie J et al.
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date accepted : 23 August 2016
                Funding
                The author(s) declared that no grants were involved in supporting this work.
                Categories
                Subject: Review
                Subject: Articles
                Subject: Cancer Therapeutics
                Subject: Cell Growth & Division
                Subject: Cell Signaling
                Subject: Control of Gene Expression
                Subject: Drug Discovery & Design
                Subject: Medical Genetics
                Subject: Membranes & Sorting
                Subject: Pharmacokinetics & Drug Delivery

                Keywords: mtor,rapamycin,mtor inhibitors,cancer therapy
                Data availability:
                Keywords: mtor, rapamycin, mtor inhibitors, cancer therapy

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