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You eat what you are: autophagy inhibition as a therapeutic strategy in leukemia

Leukemia volume 29, pages 517–525 (2015)Cite this article

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Abstract

A deeper understanding of the role of autophagy, literally ‘self-eating’, in normal and cancer cell biology has emerged over the last few years. Autophagy serves as a vehicle for cells to respond to various stressors including genomic, hypoxic and nutrient stress, and to oppose mechanisms of ‘programmed’ cell death. Here, we review not only mechanisms of cell death and cell survival but also the early successes in applying autophagy inhibition strategies in solid tumors using the only currently available clinical inhibitor, oral hydroxychloroquine. In acute leukemia, currently available chemotherapy drugs promote cell death and demonstrate clinical benefit, but relapse and subsequent chemotherapy resistance is common. Increasing preclinical data suggest that autophagy is active in leukemia as a means of promoting cell survival in response to chemotherapy. We propose coupling autophagy inhibition strategies with current cytotoxic chemotherapy and discuss synergistic combinations of available anti-leukemic therapies with autophagy inhibition. Furthermore, novel autophagy inhibitors are in development and promise to provide new therapeutic opportunities for patients with leukemia.

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Acknowledgements

This work was supported by National Institutes of Health grants R01CA181450 (MTL), R01CA160417 (DT) and R01CA137260 (DJ).

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Authors and Affiliations

  1. Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA

    A R Sehgal, D E Johnson & M Boyiadzis

  2. Department of Medicine, Division of Hematology and Medical Oncology, Indiana University Simon Cancer Center, Indianapolis, IN, USA

    H Konig

  3. Department of Surgery, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA

    D Tang & M T Lotze

  4. Department of Medicine, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA

    R K Amaravadi

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  1. A R Sehgal
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  2. H Konig
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  3. D E Johnson
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  4. D Tang
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  5. R K Amaravadi
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  6. M Boyiadzis
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  7. M T Lotze
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Correspondence to A R Sehgal.

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Competing interests

Co-author Ravi Amaravadi is an inventor on a patent covering Lys05 derivatives that has been licensed to a pharmaceutical company for clinical development. The remaining authors declare no conflict of interest.

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Sehgal, A., Konig, H., Johnson, D. et al. You eat what you are: autophagy inhibition as a therapeutic strategy in leukemia. Leukemia 29, 517–525 (2015). https://doi.org/10.1038/leu.2014.349

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  • DOI: https://doi.org/10.1038/leu.2014.349

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