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.
(Less)
- author
- Mohiuddin, Gazi
LU
; Moharram, Sausan A.
LU
; Marhäll, Alissa
LU
and Kazi, Julhash U.
LU
- organization
- publishing date
- 2017-04-28
- 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
- 2024-03-31 04:54:12
@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}},
}