Targeting PI3K/Akt/mTOR in AML: Rationale and Clinical Evidence.
AML
LSC
PI3K/Akt
combination treatment strategy
drug resistance
mTOR
targeted therapy
Journal
Journal of clinical medicine
ISSN: 2077-0383
Titre abrégé: J Clin Med
Pays: Switzerland
ID NLM: 101606588
Informations de publication
Date de publication:
11 Sep 2020
11 Sep 2020
Historique:
received:
14
08
2020
revised:
07
09
2020
accepted:
10
09
2020
entrez:
16
9
2020
pubmed:
17
9
2020
medline:
17
9
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32932888
pii: jcm9092934
doi: 10.3390/jcm9092934
pmc: PMC7563273
pii:
doi:
Types de publication
Journal Article
Review
Langues
eng
Subventions
Organisme : AIRCRAFT
ID : 19186
Organisme : the Wellcome Trust
ID : 105614/Z/14/Z
Organisme : Leukaemia UK
ID : 2016/JGF/0005
Organisme : the Howat Foundation and Friends of Paul O'Gorman
ID : SC040922
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