Oncotarget

Research Papers:

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

Seraina Faes _, Anne Planche, Emilie Uldry, Tania Santoro, Catherine Pythoud, Jean-Christophe Stehle, Janine Horlbeck, Igor Letovanec, Nicolo Riggi, Dipak Datta, Nicolas Demartines and Olivier Dormond

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Oncotarget. 2016; 7:36666-36680. https://doi.org/10.18632/oncotarget.9134

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Abstract

Seraina Faes1, Anne Planche1, Emilie Uldry1, Tania Santoro1, Catherine Pythoud1, Jean-Christophe Stehle2, Janine Horlbeck2, Igor Letovanec3, Nicolo Riggi3, Dipak Datta4,5, Nicolas Demartines1, Olivier Dormond1

1Department of Visceral Surgery, University Hospital and University of Lausanne, Lausanne, Switzerland

2Mouse Pathology Facility, University Hospital and University of Lausanne, Lausanne, Switzerland

3Institute of Pathology, University Hospital and University of Lausanne, Lausanne, Switzerland

4Biochemistry Division, CSIR-Central Drug Research Institute, Lucknow, India

5Academy of Scientific and Innovative Research, New Delhi, India

Correspondence to:

Seraina Faes, e-mail: [email protected]

Olivier Dormond, e-mail: [email protected]

Keywords: mTOR, CAIX, hypoxia, rapamycin, acetazolamide

Received: December 13, 2015    Accepted: April 18, 2016    Published: May 2, 2016

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.


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