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

Détails

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Etat: Serval
Version: Final published version
ID Serval
serval:BIB_EF4FEB78431B
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Targeting carbonic anhydrase IX improves the anti-cancer efficacy of mTOR inhibitors.
Périodique
Oncotarget
Auteur(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
Statut éditorial
Publié
Date de publication
14/06/2016
Peer-reviewed
Oui
Volume
7
Numéro
24
Pages
36666-36680
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Résumé
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.

Mots-clé
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
Oui
Création de la notice
09/05/2016 14:14
Dernière modification de la notice
09/05/2019 3:12
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