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The dual specificity PI3K/mTOR inhibitor PKI-587 displays efficacy against T-cell acute lymphoblastic leukemia (T-ALL)

Mohiuddin, Gazi LU ; Moharram, Sausan A. LU ; Marhäll, Alissa LU and Kazi, Julhash U. LU (2017) In Cancer Letters 392. p.9-16
Abstract

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... (More)

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.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Gedatolisib, Leukemia, PF 05212384, PI3K/mTOR, T-ALL
in
Cancer Letters
volume
392
pages
8 pages
publisher
Elsevier
external identifiers
  • scopus:85011949060
  • wos:000396949600002
ISSN
0304-3835
DOI
10.1016/j.canlet.2017.01.035
language
English
LU publication?
yes
id
0ec316eb-ae21-402e-9229-d8076948cd6a
date added to LUP
2017-02-27 08:28:25
date last changed
2018-07-08 04:21:49
@article{0ec316eb-ae21-402e-9229-d8076948cd6a,
  abstract     = {<p>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.</p>},
  author       = {Mohiuddin, Gazi and Moharram, Sausan A. and Marhäll, Alissa and Kazi, Julhash U.},
  issn         = {0304-3835},
  keyword      = {Gedatolisib,Leukemia,PF 05212384,PI3K/mTOR,T-ALL},
  language     = {eng},
  month        = {04},
  pages        = {9--16},
  publisher    = {Elsevier},
  series       = {Cancer Letters},
  title        = {The dual specificity PI3K/mTOR inhibitor PKI-587 displays efficacy against T-cell acute lymphoblastic leukemia (T-ALL)},
  url          = {http://dx.doi.org/10.1016/j.canlet.2017.01.035},
  volume       = {392},
  year         = {2017},
}