Dual Inhibition of PI3K and mTORC1/2 Signaling by NVP-BEZ235 as a New Therapeutic Strategy for Acute Myeloid Leukemia

@article{Chapuis2010DualIO,
  title={Dual Inhibition of PI3K and mTORC1/2 Signaling by NVP-BEZ235 as a New Therapeutic Strategy for Acute Myeloid Leukemia},
  author={Nicolas Chapuis and J{\'e}r{\^o}me Tamburini and Alexa Samantha Green and Christine Vignon and Val{\'e}rie Bardet and Aymeric Neyret and M{\'e}lanie Pannetier and Lise Willems and Sophie Park and Alexandre Macone and Sauveur Michel Maira and Norbert Ifrah and François Dreyfus and Olivier H{\'e}rault and Catherine Lacombe and Patrick Mayeux and Didier Bouscary},
  journal={Clinical Cancer Research},
  year={2010},
  volume={16},
  pages={5424 - 5435}
}
Purpose: 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… 
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Cell cycle-dependent activity of the novel dual PI3K-MTORC1/2 inhibitor NVP-BGT226 in acute leukemia
TLDR
It is shown that phosphorylation of AKT is frequently augmented in acute leukemia, which translates into potent antiproliferative effects for NVP-BGT226 and surprisingly and in contrast,NVP-BEZ235 leads to a profound G1/G0 arrest preventing significant induction of apoptosis, which provides a strong rationale for clinical evaluation of the dual PI3K-MTORC1/2 inhibitors.
Differential Effects of Selective Inhibitors Targeting the PI3K/AKT/mTOR Pathway in Acute Lymphoblastic Leukemia
TLDR
Inhibition of the PI3K/mTOR pathway is a promising therapeutic approach in patients with B-precursor ALL and greater antileukemic activity of dual PI3MTORC1/C2 inhibitors appears to be due to the redundant function ofPI3K and mTOR.
Dueling for dual inhibition: Means to enhance effectiveness of PI3K/Akt/mTOR inhibitors in AML.
Two hits are better than one: targeting both phosphatidylinositol 3-kinase and mammalian target of rapamycin as a therapeutic strategy for acute leukemia treatment
TLDR
The evidence documenting that dual PI3K/mTOR inhibitors may represent a promising option for future targeted therapies of acute leukemia patients is reviewed.
Dual PI3K/mTOR inhibition shows antileukemic activity in MLL-rearranged acute myeloid leukemia
TLDR
In vivo PI3K/mTOR inhibition delayed tumor progression, reduced tumor load and prolonged survival in an MLL-AF9+/FLT3-ITD+ xenograft mouse model and in vitro studies combining PI3k/m TOR and ERK pathway inhibition revealed highly synergistic effects in apoptosis assays implicate a possible therapeutic benefit of PI3 kappa-mutated subgroup.
PI3K and mTOR Signaling Pathways in Cancer: New Data on Targeted Therapies
TLDR
Second-generation catalytic mTOR inhibitors targeting both mTOR complexes 1 and 2 have been developed and some of them also inhibit class IA PI3K, highlighting their potential as anti-cancer drugs.
Selective targeting of the mTORC1/2 protein kinase complexes leads to antileukemic effects in vitro and in vivo
TLDR
It is determined that dual inhibition of PI3K/mTOR causes growth arrest and apoptosis leading to profound antileukemic effects both in vitro and in vivo.
The dual mTORC1 and mTORC2 inhibitor AZD8055 has anti-tumor activity in acute myeloid leukemia
TLDR
AZD8055 decreased AML blast cell proliferation and cell cycle progression, reduced the clonogenic growth of leukemic progenitors and induced caspase-dependent apoptosis inLeukemic cells but not in normal immature CD34+ cells, and induced autophagy, which may be either protective or cell death inducing, depending on concentration.
Role of mTOR signaling pathway in acute myeloid leukemia
TLDR
The role of mTOR pathway in AML is complicated and needs further investigation, while the combination of inhibitors or cytotoxic drugs acquire stronger inhibitive effect.
Chemical Therapeutics Dual PI 3 K / AKT / mTOR Inhibitor BEZ 235 Synergistically Enhances the Activity of JAK 2 Inhibitor against Cultured and Primary Human Myeloproliferative Neoplasm Cells
TLDR
Treatment with the dual phosphoinositide-3-kinase (PI3K)/AKT and mTOR inhibitor BEZ235 attenuated PI3K/AKT/mTOR signaling, as well as induced cell-cycle growth arrest and apoptosis of the cultured human JAK2-V617F-expressing HEL92.1.7.7 cells.
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