PMID- 28159681
OWN - NLM
STAT- MEDLINE
DCOM- 20170807
LR  - 20211204
IS  - 1872-7980 (Electronic)
IS  - 0304-3835 (Linking)
VI  - 392
DP  - 2017 Apr 28
TI  - The dual specificity PI3K/mTOR inhibitor PKI-587 displays efficacy against T-cell 
      acute lymphoblastic leukemia (T-ALL).
PG  - 9-16
LID - S0304-3835(17)30077-0 [pii]
LID - 10.1016/j.canlet.2017.01.035 [doi]
AB  - Although significant improvements have been made in the treatment of acute 
      lymphoblastic leukemia (ALL), there is a substantial subset of high-risk T-cell 
      ALL (T-ALL) patients with relatively poor prognosis. Like in other leukemia 
      types, alterations of the PI3K/mTOR pathway are predominant in ALL which is also 
      responsible for treatment failure and relapse. In this study, we show that 
      relapsed T-ALL patients display an enrichment of the PI3K/mTOR pathway. Using a 
      panel of inhibitors targeting multiple components of the PI3K/mTOR pathway, we 
      observed that the dual-specific PI3K/mTOR inhibitor PKI-587 was the most 
      selective inhibitor for T-ALL cells dependent on the PI3K/mTOR pathway. 
      Furthermore, we observed that PKI-587 blocked proliferation and colony formation 
      of T-ALL cell lines. Additionally, PKI-587 selectively abrogated PI3K/mTOR 
      signaling without affecting MAPK signaling both in in vitro and in vivo. 
      Inhibition of the PI3K/mTOR pathway using PKI-587 delayed tumor progression, 
      reduced tumor load and enhanced the survival rate in immune-deficient mouse 
      xenograft models without inducing weight loss in the inhibitor treated mice. This 
      preclinical study shows beneficial effects of PKI-587 on T-ALL that warrants 
      further investigation in the clinical setting.
CI  - Copyright (c) 2017 Elsevier B.V. All rights reserved.
FAU - Gazi, Mohiuddin
AU  - Gazi M
AD  - Division of Translational Cancer Research, Department of Laboratory Medicine, 
      Lund University, Lund, Sweden; Lund Stem Cell Center, Department of Laboratory 
      Medicine, Lund University, Lund, Sweden.
FAU - Moharram, Sausan A
AU  - Moharram SA
AD  - Division of Translational Cancer Research, Department of Laboratory Medicine, 
      Lund University, Lund, Sweden; Lund Stem Cell Center, Department of Laboratory 
      Medicine, Lund University, Lund, Sweden.
FAU - Marhall, Alissa
AU  - Marhall A
AD  - Division of Translational Cancer Research, Department of Laboratory Medicine, 
      Lund University, Lund, Sweden; Lund Stem Cell Center, Department of Laboratory 
      Medicine, Lund University, Lund, Sweden.
FAU - Kazi, Julhash U
AU  - Kazi JU
AD  - Division of Translational Cancer Research, Department of Laboratory Medicine, 
      Lund University, Lund, Sweden; Lund Stem Cell Center, Department of Laboratory 
      Medicine, Lund University, Lund, Sweden. Electronic address: 
      kazi.uddin@med.lu.se.
LA  - eng
PT  - Journal Article
DEP - 20170201
PL  - Ireland
TA  - Cancer Lett
JT  - Cancer letters
JID - 7600053
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Morpholines)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Triazines)
RN  - 96265TNH2R (gedatolisib)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.137 (Phosphatidylinositol 3-Kinase)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
EIN - Cancer Lett. 2019 Oct 1;461:155. PMID: 31174904
MH  - Animals
MH  - Antineoplastic Agents/*pharmacology
MH  - Cell Proliferation/drug effects
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Humans
MH  - Jurkat Cells
MH  - Mice, Inbred NOD
MH  - Mice, SCID
MH  - Molecular Targeted Therapy
MH  - Morpholines/*pharmacology
MH  - Phosphatidylinositol 3-Kinase/genetics/metabolism
MH  - *Phosphoinositide-3 Kinase Inhibitors
MH  - Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/*drug 
      therapy/enzymology/genetics/pathology
MH  - Protein Interaction Maps
MH  - Protein Kinase Inhibitors/*pharmacology
MH  - Signal Transduction/drug effects
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors/genetics/metabolism
MH  - Time Factors
MH  - Triazines/*pharmacology
MH  - Tumor Burden/drug effects
MH  - Up-Regulation
MH  - Xenograft Model Antitumor Assays
OTO - NOTNLM
OT  - Gedatolisib
OT  - Leukemia
OT  - PF 05212384
OT  - PI3K/mTOR
OT  - T-ALL
EDAT- 2017/02/06 06:00
MHDA- 2017/08/08 06:00
CRDT- 2017/02/05 06:00
PHST- 2016/12/06 00:00 [received]
PHST- 2017/01/23 00:00 [revised]
PHST- 2017/01/24 00:00 [accepted]
PHST- 2017/02/06 06:00 [pubmed]
PHST- 2017/08/08 06:00 [medline]
PHST- 2017/02/05 06:00 [entrez]
AID - S0304-3835(17)30077-0 [pii]
AID - 10.1016/j.canlet.2017.01.035 [doi]
PST - ppublish
SO  - Cancer Lett. 2017 Apr 28;392:9-16. doi: 10.1016/j.canlet.2017.01.035. Epub 2017 
      Feb 1.