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Title: Reactivation of AKT signaling following treatment of cancer cells with PI3K inhibitors attenuates their antitumor effects

Abstract

Highlights: •PI3K inhibitors inhibit AKT only transiently. •Re-activation of AKT limits the anti-cancer effect of PI3K inhibitors. •The results suggest to combine PI3K and AKT inhibitors in cancer therapy. -- Abstract: Targeting the phosphatidylinositol-3-kinase (PI3K) is a promising approach in cancer therapy. In particular, PI3K blockade leads to the inhibition of AKT, a major downstream effector responsible for the oncogenic activity of PI3K. However, we report here that small molecule inhibitors of PI3K only transiently block AKT signaling. Indeed, treatment of cancer cells with PI3K inhibitors results in a rapid inhibition of AKT phosphorylation and signaling which is followed by the reactivation of AKT signaling after 48 h as observed by Western blot. Reactivation of AKT signaling occurs despite effective inhibition of PI3K activity by PI3K inhibitors. In addition, wortmannin, a broad range PI3K inhibitor, did not block AKT reactivation suggesting that AKT signals independently of PI3K. In a therapeutical perspective, combining AKT and PI3K inhibitors exhibit stronger anti-proliferative and pro-apoptotic effects compared to AKT or PI3K inhibitors alone. Similarly, in a tumor xenograft mouse model, concomitant PI3K and AKT blockade results in stronger anti-cancer activity compared with either blockade alone. This study shows that PI3K inhibitors only transiently inhibitmore » AKT which limits their antitumor activities. It also provides the proof of concept to combine PI3K inhibitors with AKT inhibitors in cancer therapy.« less

Authors:
; ; ; ;
Publication Date:
OSTI Identifier:
22242049
Resource Type:
Journal Article
Journal Name:
Biochemical and Biophysical Research Communications
Additional Journal Information:
Journal Volume: 438; Journal Issue: 1; Other Information: Copyright (c) 2013 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0006-291X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; INHIBITION; MICE; MOLECULES; NEOPLASMS; PHOSPHORYLATION; REGENERATION; THERAPY

Citation Formats

Dufour, Marc, Dormond-Meuwly, Anne, Pythoud, Catherine, Demartines, Nicolas, and Dormond, Olivier. Reactivation of AKT signaling following treatment of cancer cells with PI3K inhibitors attenuates their antitumor effects. United States: N. p., 2013. Web. doi:10.1016/J.BBRC.2013.07.014.
Dufour, Marc, Dormond-Meuwly, Anne, Pythoud, Catherine, Demartines, Nicolas, & Dormond, Olivier. Reactivation of AKT signaling following treatment of cancer cells with PI3K inhibitors attenuates their antitumor effects. United States. https://doi.org/10.1016/J.BBRC.2013.07.014
Dufour, Marc, Dormond-Meuwly, Anne, Pythoud, Catherine, Demartines, Nicolas, and Dormond, Olivier. 2013. "Reactivation of AKT signaling following treatment of cancer cells with PI3K inhibitors attenuates their antitumor effects". United States. https://doi.org/10.1016/J.BBRC.2013.07.014.
@article{osti_22242049,
title = {Reactivation of AKT signaling following treatment of cancer cells with PI3K inhibitors attenuates their antitumor effects},
author = {Dufour, Marc and Dormond-Meuwly, Anne and Pythoud, Catherine and Demartines, Nicolas and Dormond, Olivier},
abstractNote = {Highlights: •PI3K inhibitors inhibit AKT only transiently. •Re-activation of AKT limits the anti-cancer effect of PI3K inhibitors. •The results suggest to combine PI3K and AKT inhibitors in cancer therapy. -- Abstract: Targeting the phosphatidylinositol-3-kinase (PI3K) is a promising approach in cancer therapy. In particular, PI3K blockade leads to the inhibition of AKT, a major downstream effector responsible for the oncogenic activity of PI3K. However, we report here that small molecule inhibitors of PI3K only transiently block AKT signaling. Indeed, treatment of cancer cells with PI3K inhibitors results in a rapid inhibition of AKT phosphorylation and signaling which is followed by the reactivation of AKT signaling after 48 h as observed by Western blot. Reactivation of AKT signaling occurs despite effective inhibition of PI3K activity by PI3K inhibitors. In addition, wortmannin, a broad range PI3K inhibitor, did not block AKT reactivation suggesting that AKT signals independently of PI3K. In a therapeutical perspective, combining AKT and PI3K inhibitors exhibit stronger anti-proliferative and pro-apoptotic effects compared to AKT or PI3K inhibitors alone. Similarly, in a tumor xenograft mouse model, concomitant PI3K and AKT blockade results in stronger anti-cancer activity compared with either blockade alone. This study shows that PI3K inhibitors only transiently inhibit AKT which limits their antitumor activities. It also provides the proof of concept to combine PI3K inhibitors with AKT inhibitors in cancer therapy.},
doi = {10.1016/J.BBRC.2013.07.014},
url = {https://www.osti.gov/biblio/22242049}, journal = {Biochemical and Biophysical Research Communications},
issn = {0006-291X},
number = 1,
volume = 438,
place = {United States},
year = {Fri Aug 16 00:00:00 EDT 2013},
month = {Fri Aug 16 00:00:00 EDT 2013}
}