Targeting carbonic anhydrase IX improves the anti-cancer efficacy of mTOR inhibitors.

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State: Public
Version: Final published version
Serval ID
serval:BIB_EF4FEB78431B
Type
Article: article from journal or magazin.
Collection
Publications
Title
Targeting carbonic anhydrase IX improves the anti-cancer efficacy of mTOR inhibitors.
Journal
Oncotarget
Author(s)
Faes S., Planche A., Uldry E., Santoro T., Pythoud C., Stehle J.C., Horlbeck J., Letovanec I., Riggi N., Datta D., Demartines N., Dormond O.
ISSN
1949-2553 (Electronic)
ISSN-L
1949-2553
Publication state
Published
Issued date
14/06/2016
Peer-reviewed
Oui
Volume
7
Number
24
Pages
36666-36680
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
The inhibition of the mechanistic target of rapamycin complex 1 (mTORC1) by chemical inhibitors, such as rapamycin, has demonstrated anti-cancer activity in preclinical and clinical trials. Their efficacy is, however, limited and tumors eventually relapse through resistance formation. In this study, using two different cancer mouse models, we identify tumor hypoxia as a novel mechanism of resistance of cancer cells against mTORC1 inhibitors. Indeed, we show that the activity of mTORC1 is mainly restricted to the non-hypoxic tumor compartment, as evidenced by a mutually exclusive staining pattern of the mTORC1 activity marker pS6 and the hypoxia marker pimonidazole. Consequently, whereas rapamycin reduces cancer cell proliferation in non-hypoxic regions, it has no effect in hypoxic areas, suggesting that cancer cells proliferate independently of mTORC1 under hypoxia. Targeting the hypoxic tumor compartment by knockdown of carbonic anhydrase IX (CAIX) using short hairpin RNA or by chemical inhibition of CAIX with acetazolamide potentiates the anti-cancer activity of rapamycin. Taken together, these data emphasize that hypoxia impairs the anti-cancer efficacy of rapalogs. Therapeutic strategies targeting the hypoxic tumor compartment, such as the inhibition of CAIX, potentiate the efficacy of rapamycin and warrant further clinical evaluation.

Keywords
Acetazolamide/pharmacology, Animals, Antibiotics, Antineoplastic/pharmacology, Carbonic Anhydrase IX/antagonists & inhibitors, Carbonic Anhydrase IX/genetics, Carbonic Anhydrase IX/metabolism, Carbonic Anhydrase Inhibitors/pharmacology, Cell Line, Tumor, Colorectal Neoplasms/drug therapy, Colorectal Neoplasms/genetics, Colorectal Neoplasms/metabolism, Drug Synergism, Female, HT29 Cells, Humans, Hypoxia, Mice, Inbred C57BL, Mice, Nude, Neoplasms, Experimental/drug therapy, Neoplasms, Experimental/genetics, Neoplasms, Experimental/metabolism, RNA Interference, Sirolimus/pharmacology, TOR Serine-Threonine Kinases/antagonists & inhibitors, TOR Serine-Threonine Kinases/metabolism, Treatment Outcome, Xenograft Model Antitumor Assays, CAIX, acetazolamide, hypoxia, mTOR, rapamycin
Pubmed
Web of science
Open Access
Yes
Create date
09/05/2016 14:14
Last modification date
20/08/2019 17:17
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