Targeting carbonic anhydrase IX improves the anti-cancer efficacy of mTOR inhibitors
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Seraina Faes1, Anne Planche1, Emilie Uldry1
1Department of Visceral Surgery, University Hospital and University of Lausanne, Lausanne, Switzerland.
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.
Insights
Tumor hypoxia causes resistance to mTORC1 inhibitors like rapamycin by allowing cancer cells to proliferate independently of this pathway. Targeting hypoxia, for example by inhibiting carbonic anhydrase IX (CAIX), enhances anti-cancer effects.
Area of Science:
- Oncology
- Cancer Biology
- Molecular Medicine
Background:
- Mechanistic target of rapamycin complex 1 (mTORC1) inhibitors show anti-cancer activity but face limited efficacy due to acquired resistance.
- Tumor relapse is a common challenge, necessitating the identification of novel resistance mechanisms.
Purpose of the Study:
- To investigate tumor hypoxia as a novel mechanism of resistance to mTORC1 inhibitors.
- To evaluate therapeutic strategies targeting hypoxic tumor regions to overcome resistance.
Main Methods:
- Utilized two distinct cancer mouse models.
- Assessed mTORC1 activity using pS6 staining and hypoxia using pimonidazole staining.
- Investigated the role of carbonic anhydrase IX (CAIX) by knockdown (shRNA) and chemical inhibition (acetazolamide).
Main Results:
- mTORC1 activity (pS6) was predominantly observed in non-hypoxic tumor regions, mutually exclusive with hypoxia markers.
- Rapamycin inhibited proliferation in non-hypoxic areas but not in hypoxic regions.
- Targeting CAIX in hypoxic areas potentiated the anti-cancer effects of rapamycin.
Conclusions:
- Hypoxia is a significant mechanism of resistance to mTORC1 inhibitors, impairing their efficacy.
- Therapeutic strategies targeting the hypoxic tumor compartment, such as CAIX inhibition, can enhance the effectiveness of rapamycin.
- Combined approaches targeting hypoxia warrant further clinical investigation for improved cancer therapy.
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