Dual inhibition of PI3K and mTORC1/2 signaling by NVP-BEZ235 as a new therapeutic strategy for acute myeloid leukemia.
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.
Chapuis
Nicolas
N
Institut Cochin, Université Paris Descartes, CNRS (UMR8104)/INSERM U1016; Service d'Hématologie Biologique, Hôpital Cochin, AP-HP, Paris, France.
Tamburini
Jerome
J
Green
Alexa S
AS
Vignon
Christine
C
Bardet
Valerie
V
Neyret
Aymeric
A
Pannetier
Melanie
M
Willems
Lise
L
Park
Sophie
S
Macone
Alexandre
A
Maira
Sauveur-Michel
SM
Ifrah
Norbert
N
Dreyfus
François
F
Herault
Olivier
O
Lacombe
Catherine
C
Mayeux
Patrick
P
Bouscary
Didier
D
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
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