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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 orcid (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
; ; and
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
  • pmid:28159681
  • wos:000396949600002
  • scopus:85011949060
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
2024-10-14 01:22:53
@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}},
  keywords     = {{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          = {{https://lup.lub.lu.se/search/files/28760244/21968202.pdf}},
  doi          = {{10.1016/j.canlet.2017.01.035}},
  volume       = {{392}},
  year         = {{2017}},
}