Journal
LEUKEMIA
Volume 27, Issue 3, Pages 650-660Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2012.285
Keywords
PI3K; NOTCH; c-MYC; T-cell
Categories
Funding
- NIHR Biomedical Research Centres funding scheme of the UK Department of Health
- Leukaemia and Lymphoma Research, UK
- Kay Kendall Leukaemia Fund
- Medical Research Council UK
- Tapner ALL Research Fund
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PI3K, mTOR and NOTCH pathways are frequently dysregulated in T-cell acute lymphoblastic leukaemia (T-ALL). Blockade of PI3K and mTOR with the dual inhibitor PI-103 decreased proliferation in all 15 T-ALL cell lines tested, inducing cell death in three. Combined PI3K/mTOR/NOTCH inhibition (with a gamma-secretase inhibitor (GSI)) led to enhanced cell-cycle arrest and to subsequent cell death in 7/11 remaining NOTCH mutant cell lines. Commitment to cell death occurred within 48-72 h and was maximal when PI3K, mTOR and NOTCH activities were inhibited. PI-103 addition led to upregulation of c-MYC, which was blocked by coincubation with a GSI, indicating that PI3K/mTOR inhibition resulted in activation of the NOTCH-MYC pathway. Microarray studies showed a global increase in NOTCH target gene expression upon PI3K/mTOR inhibition. NOTCH-MYC-induced resistance to PI3K/nnTOR inhibition was supported by synergistic cell death induction by PI-103 and a small molecule c-MYC inhibitor, and by reduction of the cytotoxic effect of PI-103 + GSI by c-MYC overexpression. These results show that drugs targeting PI3K/mTOR can upregulate NOTCH-MYC activity, have implications for the use of PI3K inhibitors for the treatment of other malignancies with activated NOTCH, and provide a rational basis for the use of drug combinations that target both the pathways. Leukemia (2013) 27, 650-660; doi:10.1038/leu.2012.285
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