Rebound pathway overactivation by cancer cells following discontinuation of PI3K or mTOR inhibition promotes cancer cell growth.
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Serval ID
serval:BIB_EE9065608CC6
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Rebound pathway overactivation by cancer cells following discontinuation of PI3K or mTOR inhibition promotes cancer cell growth.
Journal
Biochemical and biophysical research communications
ISSN
1090-2104 (Electronic)
ISSN-L
0006-291X
Publication state
Published
Issued date
04/06/2019
Peer-reviewed
Oui
Volume
513
Number
3
Pages
546-552
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Abstract
Whilst effects of anti-cancer drugs have been thoroughly explored, little is known about the repercussion of drug cessation. However, this has important clinical relevance since several clinical protocols such as intermittent drug scheduling lead to frequent drug discontinuation. In this study, we have thus investigated the consequences of withdrawal of agents that target the PI3K/AKT/mTOR signaling pathway in cancer cells. We report that washout of kinase inhibitors of mTOR or PI3K inhibitors led to a rapid and sustainable overactivation of AKT. Consequently, proliferation of tumor cells was significantly higher following drug washout in cancer cells that were pre-treated with mTOR or PI3K inhibitors compared to untreated cells. This effect was prevented by the addition of an AKT inhibitor following drug washout. Rebound AKT overactivation induced by mTOR or PI3K inhibitors discontinuation was mediated by IGF-1R, as demonstrated by its prevention in the presence of an IGF-1R inhibitor and by increased IGF-1R phosphorylation in treated cells versus control cells. Taken together, our results show that discontinuation of PI3K or mTOR inhibitors results in AKT overactivation that promotes tumor growth. They further highlight the benefit of adding an AKT inhibitor following cessation of PI3K or mTOR inhibitors.
Keywords
Antineoplastic Agents/pharmacology, Cell Line, Tumor, Cell Proliferation, HT29 Cells, Heterocyclic Compounds, 3-Ring/pharmacology, Humans, Neoplasms/enzymology, Neoplasms/pathology, Phosphoinositide-3 Kinase Inhibitors/pharmacology, Protein Kinase Inhibitors/pharmacology, Proto-Oncogene Proteins c-akt/antagonists & inhibitors, Proto-Oncogene Proteins c-akt/metabolism, Receptor, IGF Type 1/antagonists & inhibitors, TOR Serine-Threonine Kinases/antagonists & inhibitors, Cancer, PI3K, Targeted therapies, Washout, mTOR
Pubmed
Web of science
Open Access
Yes
Create date
28/04/2019 16:00
Last modification date
21/11/2022 9:29