title: Targeting carbonic anhydrase IX improves the anti-cancer efficacy of mTOR inhibitors.
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.
authors.affiliation: Department of Visceral Surgery, University Hospital and University of Lausanne, Lausanne, Switzerland.
authors.forename: Seraina
authors.initials: S
authors.lastname: Faes
authors.affiliation: Department of Visceral Surgery, University Hospital and University of Lausanne, Lausanne, Switzerland.
authors.forename: Anne
authors.initials: A
authors.lastname: Planche
authors.affiliation: Department of Visceral Surgery, University Hospital and University of Lausanne, Lausanne, Switzerland.
authors.forename: Emilie
authors.initials: E
authors.lastname: Uldry
authors.affiliation: Department of Visceral Surgery, University Hospital and University of Lausanne, Lausanne, Switzerland.
authors.forename: Tania
authors.initials: T
authors.lastname: Santoro
authors.affiliation: Department of Visceral Surgery, University Hospital and University of Lausanne, Lausanne, Switzerland.
authors.forename: Catherine
authors.initials: C
authors.lastname: Pythoud
authors.affiliation: Mouse Pathology Facility, University Hospital and University of Lausanne, Lausanne, Switzerland.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Stehle
authors.affiliation: Mouse Pathology Facility, University Hospital and University of Lausanne, Lausanne, Switzerland.
authors.forename: Janine
authors.initials: J
authors.lastname: Horlbeck
authors.affiliation: Institute of Pathology, University Hospital and University of Lausanne, Lausanne, Switzerland.
authors.forename: Igor
authors.initials: I
authors.lastname: Letovanec
authors.affiliation: Institute of Pathology, University Hospital and University of Lausanne, Lausanne, Switzerland.
authors.forename: Nicolo
authors.initials: N
authors.lastname: Riggi
authors.affiliation: Biochemistry Division, CSIR-Central Drug Research Institute, Lucknow, India.|Academy of Scientific and Innovative Research, New Delhi, India.
authors.forename: Dipak
authors.initials: D
authors.lastname: Datta
authors.affiliation: Department of Visceral Surgery, University Hospital and University of Lausanne, Lausanne, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Demartines
authors.affiliation: Department of Visceral Surgery, University Hospital and University of Lausanne, Lausanne, Switzerland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Dormond
mesh_terms: D000086:Acetazolamide / Q000494:pharmacology*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000071231:Carbonic Anhydrase IX / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D004357:Drug Synergism; D005260:Female; D019073:HT29 Cells; D006801:Humans; D000860:Hypoxia; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D002257:Carbonic Anhydrase Inhibitors; D058570:TOR Serine-Threonine Kinases; D000071231:Carbonic Anhydrase IX; D000086:Acetazolamide; D020123:Sirolimus
keywords: CAIX; acetazolamide; hypoxia; mTOR; rapamycin