Targeting PI3K/Akt/mTOR in AML: Rationale and Clinical Evidence

Acute myeloid leukemia (AML) is a highly heterogeneous hematopoietic malignancy characterized by excessive proliferation and accumulation of immature myeloid blasts in the bone marrow. AML has a very poor 5-year survival rate of just 16% in the UK; hence, more efficacious, tolerable, and targeted th...

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Bibliographic Details
Published in:Journal of clinical medicine 2020-09, Vol.9 (9), p.2934
Main Authors: Darici, Salihanur, Alkhaldi, Hazem, Horne, Gillian, Jørgensen, Heather G, Marmiroli, Sandra, Huang, Xu
Format: Article
Language:English
Subjects:
Apoptosis
Cell cycle
Cell growth
Chemotherapy
Clinical medicine
Genes
Kinases
Leukemia
Mutation
Phosphatase
Phosphorylation
Proteins
Regulation
Review
Stem cells
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Summary:Acute myeloid leukemia (AML) is a highly heterogeneous hematopoietic malignancy characterized by excessive proliferation and accumulation of immature myeloid blasts in the bone marrow. AML has a very poor 5-year survival rate of just 16% in the UK; hence, more efficacious, tolerable, and targeted therapy is required. Persistent leukemia stem cell (LSC) populations underlie patient relapse and development of resistance to therapy. Identification of critical oncogenic signaling pathways in AML LSC may provide new avenues for novel therapeutic strategies. The phosphatidylinositol-3-kinase (PI3K)/Akt and the mammalian target of rapamycin (mTOR) signaling pathway, is often hyperactivated in AML, required to sustain the oncogenic potential of LSCs. Growing evidence suggests that targeting key components of this pathway may represent an effective treatment to kill AML LSCs. Despite this, accruing significant body of scientific knowledge, PI3K/Akt/mTOR inhibitors have not translated into clinical practice. In this article, we review the laboratory-based evidence of the critical role of PI3K/Akt/mTOR pathway in AML, and outcomes from current clinical studies using PI3K/Akt/mTOR inhibitors. Based on these results, we discuss the putative mechanisms of resistance to PI3K/Akt/mTOR inhibition, offering rationale for potential candidate combination therapies incorporating PI3K/Akt/mTOR inhibitors for precision medicine in AML.
ISSN:2077-0383
2077-0383
DOI:10.3390/jcm9092934