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The PI3K-mTOR Pathway

  • Chapter
mTOR Inhibition for Cancer Therapy: Past, Present and Future

Abstract

Phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling is required for normal development, growth, and physiology. Mutations in multiple key regulators of this pathway have been reported to occur leading to aberrant signaling and have been implicated in a number of pathologies, including metabolic syndrome. This chapter will review the major proteins involved in PI3K/mTOR signaling and discuss the negative feedback loops which maintain homeostasis. The therapeutic advantages and limitations of PI3K and/or catalytic mTOR inhibitors, which are currently in clinical development, will be discussed. We also report studies using these inhibitors along with genetic models to delete or overexpress key players in PI3K/mTOR signaling pathways in yeast, worms, drosophila, and mice, which have been instrumental in elucidating the functions of these proteins in normal and disease states. Particular attention has been focused on the role of PI3K/mTOR signaling in proliferation, translation, metabolism (including energy balance regulation and metabolic syndrome), autophagy, and differentiation.

$Author contributed equally with all other contributors.

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Acknowledgments

We are thankful to G. Doerman for the assistance with preparation of figures. H.E.T is supported by a faculty pilot project grant by the Department of Internal Medicine, University of Cincinnati, OH. G.T. is supported by grants from the Instituto de Salud Carlos III (IIS10/00015), the Spanish Ministry of Science and Innovation (SAF2014-52162), the CIG European Commission (PCIG10-GA-2011-304160), and the NIH/NCI National Cancer Institute (R01-CA158768). S.C.K is supported by grants from the Instituto de Salud Carlos III (IIS12/00002) GT and SCK are also supported by the European Regional Development Fund FEDER in Spain and from the Spanish Ministry of Economy and Competitivity (BFU2012-38867).

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    1. Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, USA

      Hala Elnakat Thomas, George Thomas & Sara C. Kozma

    2. Laboratory of Cancer Metabolism, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute, Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), Hospitalet de Llobregat, Barcelona, 08908, Spain

      Sónia R. Pereira da Veiga, George Thomas & Sara C. Kozma

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    1. Samuel Oschin Comprehensive Cancer Inst Cedars Sinai Medical Center, Los Angeles, California, USA

      Monica Mita

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      Eric K. Rowinsky

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    Thomas, H.E., da Veiga, S.R.P., Thomas, G., Kozma, S.C. (2016). The PI3K-mTOR Pathway. In: Mita, M., Mita, A., Rowinsky, E. (eds) mTOR Inhibition for Cancer Therapy: Past, Present and Future. Springer, Paris. https://doi.org/10.1007/978-2-8178-0492-7_2

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