PMID- 32932888
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20201028
IS  - 2077-0383 (Print)
IS  - 2077-0383 (Electronic)
IS  - 2077-0383 (Linking)
VI  - 9
IP  - 9
DP  - 2020 Sep 11
TI  - Targeting PI3K/Akt/mTOR in AML: Rationale and Clinical Evidence.
LID - 10.3390/jcm9092934 [doi]
LID - 2934
AB  - 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.
FAU - Darici, Salihanur
AU  - Darici S
AD  - Haemato-Oncology/Systems Medicine Group, Paul O'Gorman Leukaemia Research Centre, 
      University of Glasgow, Glasgow G12 0ZD, UK.
AD  - Department of Biomedical, Metabolic and Neural Sciences, University of Modena and 
      Reggio Emilia, 41124 Modena, Italy.
FAU - Alkhaldi, Hazem
AU  - Alkhaldi H
AD  - Haemato-Oncology/Systems Medicine Group, Paul O'Gorman Leukaemia Research Centre, 
      University of Glasgow, Glasgow G12 0ZD, UK.
FAU - Horne, Gillian
AU  - Horne G
AD  - Haemato-Oncology/Systems Medicine Group, Paul O'Gorman Leukaemia Research Centre, 
      University of Glasgow, Glasgow G12 0ZD, UK.
FAU - Jorgensen, Heather G
AU  - Jorgensen HG
AUID- ORCID: 0000-0003-4663-4191
AD  - Haemato-Oncology/Systems Medicine Group, Paul O'Gorman Leukaemia Research Centre, 
      University of Glasgow, Glasgow G12 0ZD, UK.
FAU - Marmiroli, Sandra
AU  - Marmiroli S
AD  - Department of Biomedical, Metabolic and Neural Sciences, University of Modena and 
      Reggio Emilia, 41124 Modena, Italy.
FAU - Huang, Xu
AU  - Huang X
AUID- ORCID: 0000-0001-6706-199X
AD  - Haemato-Oncology/Systems Medicine Group, Paul O'Gorman Leukaemia Research Centre, 
      University of Glasgow, Glasgow G12 0ZD, UK.
LA  - eng
GR  - 19186/AIRCRAFT/
GR  - 105614/Z/14/Z/the Wellcome Trust/
GR  - 2016/JGF/0005/Leukaemia UK/
GR  - SC040922/the Howat Foundation and Friends of Paul O'Gorman/
PT  - Journal Article
PT  - Review
DEP - 20200911
PL  - Switzerland
TA  - J Clin Med
JT  - Journal of clinical medicine
JID - 101606588
PMC - PMC7563273
OTO - NOTNLM
OT  - AML
OT  - LSC
OT  - PI3K/Akt
OT  - combination treatment strategy
OT  - drug resistance
OT  - mTOR
OT  - targeted therapy
COIS- The authors declare no conflict of interest.
EDAT- 2020/09/17 06:00
MHDA- 2020/09/17 06:01
PMCR- 2020/09/11
CRDT- 2020/09/16 01:01
PHST- 2020/08/14 00:00 [received]
PHST- 2020/09/07 00:00 [revised]
PHST- 2020/09/10 00:00 [accepted]
PHST- 2020/09/16 01:01 [entrez]
PHST- 2020/09/17 06:00 [pubmed]
PHST- 2020/09/17 06:01 [medline]
PHST- 2020/09/11 00:00 [pmc-release]
AID - jcm9092934 [pii]
AID - jcm-09-02934 [pii]
AID - 10.3390/jcm9092934 [doi]
PST - epublish
SO  - J Clin Med. 2020 Sep 11;9(9):2934. doi: 10.3390/jcm9092934.