title: Acidic tumor microenvironment abrogates the efficacy of mTORC1 inhibitors.
abstract: Blocking the mechanistic target of rapamycin complex-1 (mTORC1) with chemical inhibitors such as rapamycin has shown limited clinical efficacy in cancer. The tumor microenvironment is characterized by an acidic pH which interferes with cancer therapies. The consequences of acidity on the anti-cancer efficacy of mTORC1 inhibitors have not been characterized and are thus the focus of our study.
  
  
  
  Cancer cell lines were treated with rapamycin in acidic or physiological conditions and cell proliferation was investigated. The effect of acidity on mTORC1 activity was determined by Western blot. The anticancer efficacy of rapamycin in combination with sodium bicarbonate to increase the intratumoral pH was tested in two different mouse models and compared to rapamycin treatment alone. Histological analysis was performed on tumor samples to evaluate proliferation, apoptosis and necrosis.
  
  
  
  Exposing cancer cells to acidic pH in vitro significantly reduced the anti-proliferative effect of rapamycin. At the molecular level, acidity significantly decreased mTORC1 activity, suggesting that cancer cell proliferation is independent of mTORC1 in acidic conditions. In contrast, the activation of mitogen-activated protein kinase (MAPK) or AKT were not affected by acidity, and blocking MAPK or AKT with a chemical inhibitor maintained an anti-proliferative effect at low pH. In tumor mouse models, the use of sodium bicarbonate increased mTORC1 activity in cancer cells and potentiated the anti-cancer efficacy of rapamycin. Combining sodium bicarbonate with rapamycin resulted in increased tumor necrosis, increased cancer cell apoptosis and decreased cancer cell proliferation as compared to single treatment.
  
  
  
  Taken together, these results emphasize the inefficacy of mTORC1 inhibitors in acidic conditions. They further highlight the potential of combining sodium bicarbonate with mTORC1 inhibitors to improve their anti-tumoral efficacy.
authors.affiliation: Lausanne University Hospital CHUV and University of Lausanne, Pavillon 4, Av. de Beaumont, 1011, Lausanne, Switzerland.
authors.forename: Seraina
authors.initials: S
authors.lastname: Faes
authors.affiliation: Lausanne University Hospital CHUV and University of Lausanne, Pavillon 4, Av. de Beaumont, 1011, Lausanne, Switzerland.|Current Address: Swiss Institute of Experimental Cancer Research (ISREC), Swiss Federal Institute of Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Adrian P
authors.initials: AP
authors.lastname: Duval
authors.affiliation: Lausanne University Hospital CHUV and University of Lausanne, Pavillon 4, Av. de Beaumont, 1011, Lausanne, Switzerland.
authors.forename: Anne
authors.initials: A
authors.lastname: Planche
authors.affiliation: Lausanne University Hospital CHUV and University of Lausanne, Pavillon 4, Av. de Beaumont, 1011, Lausanne, Switzerland.
authors.forename: Emilie
authors.initials: E
authors.lastname: Uldry
authors.affiliation: Lausanne University Hospital CHUV and University of Lausanne, Pavillon 4, Av. de Beaumont, 1011, Lausanne, Switzerland.
authors.forename: Tania
authors.initials: T
authors.lastname: Santoro
authors.affiliation: Lausanne University Hospital CHUV and University of Lausanne, Pavillon 4, Av. de Beaumont, 1011, Lausanne, Switzerland.
authors.forename: Catherine
authors.initials: C
authors.lastname: Pythoud
authors.affiliation: Mouse Pathology Facility, Lausanne University Hospital CHUV and University of Lausanne, Lausanne, Switzerland.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Stehle
authors.affiliation: Mouse Pathology Facility, Lausanne University Hospital CHUV and University of Lausanne, Lausanne, Switzerland.
authors.forename: Janine
authors.initials: J
authors.lastname: Horlbeck
authors.affiliation: Institute of Pathology, Lausanne University Hospital CHUV and University of Lausanne, Lausanne, Switzerland.
authors.forename: Igor
authors.initials: I
authors.lastname: Letovanec
authors.affiliation: Institute of Pathology, Lausanne University Hospital CHUV and University of Lausanne, Lausanne, Switzerland.
authors.forename: Nicolo
authors.initials: N
authors.lastname: Riggi
authors.affiliation: Lausanne University Hospital CHUV and University of Lausanne, Pavillon 4, Av. de Beaumont, 1011, Lausanne, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Demartines
authors.affiliation: Lausanne University Hospital CHUV and University of Lausanne, Pavillon 4, Av. de Beaumont, 1011, Lausanne, Switzerland. olivier.dormond@chuv.ch.
authors.forename: Olivier
authors.initials: O
authors.lastname: Dormond
mesh_terms: D000143:Acids / Q000009:adverse effects*; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004359:Drug Therapy, Combination; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019073:HT29 Cells; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020123:Sirolimus / Q000008:administration & dosage* / Q000494:pharmacology; D017693:Sodium Bicarbonate / Q000008:administration & dosage* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
chemical_list: D000143:Acids; D046912:Multiprotein Complexes; D017693:Sodium Bicarbonate; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Acidity; Rapamycin; Resistance Mechanisms; Sodium Bicarbonate; Tumor Microenvironment; mTORC1