title: Dual inhibition of PI3K and mTORC1/2 signaling by NVP-BEZ235 as a new therapeutic strategy for acute myeloid leukemia.
abstract: OBJECTIVE
  The growth and survival of acute myeloid leukemia (AML) cells are enhanced by the deregulation of signaling pathways such as phosphoinositide 3-kinase (PI3K)/Akt and mammalian target of rapamycin (mTOR). Major efforts have thus been made to develop molecules targeting these activated pathways. The mTOR serine/threonine kinase belongs to two separate complexes: mTORC1 and mTORC2. The mTORC1 pathway is rapamycin sensitive and controls protein translation through the phosphorylation of 4E-BP1 in most models. In AML, however, the translation process is deregulated and rapamycin resistant. Furthermore, the activity of PI3K/Akt and mTOR is closely related, as mTORC2 activates the oncogenic kinase Akt. We therefore tested, in this study, the antileukemic activity of the dual PI3K/mTOR ATP-competitive inhibitor NVP-BEZ235 compound (Novartis).
  
  
  METHODS
  The activity of NVP-BEZ235 was tested in primary AML samples (n = 21) and human leukemic cell lines. The different signaling pathways were analyzed by Western blotting. The cap-dependent mRNA translation was studied by 7-methyl-GTP pull-down experiments, polysomal analysis, and [(3)H]leucine incorporation assays. The antileukemic activity of NVP-BEZ235 was tested by analyzing its effects on leukemic progenitor clonogenicity, blast cell proliferation, and survival.
  
  
  RESULTS
  The NVP-BEZ235 compound was found to inhibit PI3K and mTORC1 signaling and also mTORC2 activity. Furthermore, NVP-BEZ235 fully inhibits the rapamycin-resistant phosphorylation of 4E-BP1, resulting in a marked inhibition of protein translation in AML cells. Hence, NVP-BEZ235 reduces the proliferation rate and induces an important apoptotic response in AML cells without affecting normal CD34(+) survival.
  
  
  CONCLUSIONS
  Our results clearly show the antileukemic efficiency of the NVP-BEZ235 compound, which therefore represents a promising option for future AML therapies.
authors.affiliation: Institut Cochin, Université Paris Descartes, CNRS (UMR8104)/INSERM U1016; Service d'Hématologie Biologique, Hôpital Cochin, AP-HP, Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chapuis
authors.forename: Jerome
authors.initials: J
authors.lastname: Tamburini
authors.forename: Alexa S
authors.initials: AS
authors.lastname: Green
authors.forename: Christine
authors.initials: C
authors.lastname: Vignon
authors.forename: Valerie
authors.initials: V
authors.lastname: Bardet
authors.forename: Aymeric
authors.initials: A
authors.lastname: Neyret
authors.forename: Melanie
authors.initials: M
authors.lastname: Pannetier
authors.forename: Lise
authors.initials: L
authors.lastname: Willems
authors.forename: Sophie
authors.initials: S
authors.lastname: Park
authors.forename: Alexandre
authors.initials: A
authors.lastname: Macone
authors.forename: Sauveur-Michel
authors.initials: SM
authors.lastname: Maira
authors.forename: Norbert
authors.initials: N
authors.lastname: Ifrah
authors.forename: François
authors.initials: F
authors.lastname: Dreyfus
authors.forename: Olivier
authors.initials: O
authors.lastname: Herault
authors.forename: Catherine
authors.initials: C
authors.lastname: Lacombe
authors.forename: Patrick
authors.initials: P
authors.lastname: Mayeux
authors.forename: Didier
authors.initials: D
authors.lastname: Bouscary
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology* / Q000627:therapeutic use; D012315:RNA Caps / Q000037:antagonists & inhibitors / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011506:Proteins; D011804:Quinolines; D012315:RNA Caps; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; C493245:CRTC2 protein, human; C531198:dactolisib