Targeting PI3K/Akt/mTOR in AML: rationale and clinical evidence

Darici, S., Alkhaldi, H., Horne, G. , Jørgensen, H. G., Marmiroli, S. and Huang, X. (2020) Targeting PI3K/Akt/mTOR in AML: rationale and clinical evidence. Journal of Clinical Medicine, 9(9), 2934. (doi: 10.3390/jcm9092934) (PMID:32932888) (PMCID:PMC7563273)

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Abstract

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

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:alkhaldi, Mr hazem and Jorgensen, Dr Heather and Huang, Dr Xu and Horne, Dr Gillian and Darici, Ms Salihanur
Authors: Darici, S., Alkhaldi, H., Horne, G., Jørgensen, H. G., Marmiroli, S., and Huang, X.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Journal of Clinical Medicine
Publisher:MDPI
ISSN:2077-0383
ISSN (Online):2077-0383
Published Online:11 September 2020
Copyright Holders:Copyright © 2020 The Authors
First Published:First published in Journal of Clinical Medicine 9(9): 2934
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
172121Funding SchemesAnna DominiczakWellcome Trust (WELLCOTR)105614/Z/14/ZInstitute of Cardiovascular & Medical Sciences
173450Delineation of the critical epigenetic regulatory machinery selective for acute myeloid leukaemia stem cell functionXu HuangLeuka (LEUKA)2016/JGF/0005CS - Paul O'Gorman Leukaemia Research Centre