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The PI3K-AKT-mTOR Signaling Network in AML

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Targeted Therapy of Acute Myeloid Leukemia

Part of the book series: Current Cancer Research ((CUCR))

Abstract

Acute myelogenous leukemia (AML) is the most common leukemia in adults. Currently, AML patients are treated mainly with combinations of cytotoxic chemotherapies. There is an urgent need for targeted therapies in AML that improve patient survival while limiting side effects. Small molecules that inhibit crucial signaling components have potential to block proliferation and survival of leukemia cells in a selective manner. A cellular signaling network involving phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), and mechanistic target of rapamycin (mTOR), is highly active in most AML cells and contains several components that are druggable. This chapter will focus on the biology of PI3K/AKT/mTOR signaling in AML cells and the potential of novel inhibitors to disrupt oncogenic pathways in leukemia cells.

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Authors and Affiliations

  1. Department of Molecular Biology & Biochemistry, University of California, Irvine, Laboratory David Fruman, McGaugh Hall, Room 3407, 92697-3900, Irvine, CA, USA

    Brandon Beagle M.D.

  2. Department of Molecular Biology & Biochemistry and Institute for Immunology, University of California, Irvine, McGaugh Hall, Room 3242, 92697-3900, Irvine, CA, USA

    Dr. David A. Fruman

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  1. Brandon Beagle M.D.
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Correspondence to David A. Fruman .

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Editors and Affiliations

  1. Dept. Leukemia, University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Michael Andreeff

Conclusion

Conclusion

Activation of the PI3K/AKT/mTOR network is now considered a hallmark of cancer cells that promotes survival and proliferation through multiple mechanisms (Hanahan and Weinberg 2011). Consistent evidence from AML cell lines and patient AML blasts clearly shows that the PI3K/AKT/mTOR network is an oncogenic driver in AML and that pharmacological targeting of the network has demonstrable antileukemic effects. Nevertheless, AML is a heterogeneous disease with multiple oncogenic mechanisms that vary among patients. As in other hematological malignancies , inhibition of a single network is not likely to provide a uniformly strong cytotoxic effect. Further studies are required to determine the most effective combinations to eradicate AML blasts and leukemia initiating cells while minimizing toxicity to normal tissue. Biomarker analysis can aid in determining which patients will benefit from a particular inhibitor combination. Genomic and proteomic strategies will help to identify patients most likely to benefit from PI3K/AKT/mTOR network suppression and which companion therapies will unleash the greatest antileukemic response.

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Beagle, B., Fruman, D. (2015). The PI3K-AKT-mTOR Signaling Network in AML. In: Andreeff, M. (eds) Targeted Therapy of Acute Myeloid Leukemia. Current Cancer Research. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1393-0_17

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