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PI3K/mTOR inhibition upregulates NOTCH-MYC signalling leading to an impaired cytotoxic response.
MedLine Citation:
PMID:  23038273     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
PI3 K, mTOR and NOTCH pathways are frequently dysregulated in T-ALL. Blockade of PI3 K and mTOR with the dual inhibitor PI-103 decreased proliferation in 15 T-ALL cell lines tested, inducing cell death in 3. 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 PI3 K, mTOR and NOTCH activities were inhibited. PI-103 addition led to upregulation of c-MYC which was blocked by co-incubation with a GSI, indicating that PI3K/mTOR inhibition resulted in activation of a NOTCH-MYC pathway. Microarray studies showed a global increase in NOTCH target gene expression upon PI3K/mTOR inhibition. NOTCH-MYC induced resistance to PI3K/mTOR 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 PI3 K inhibitors for the treatment of other malignancies with activated NOTCH, and provide a rational basis for the use of drug combinations that target both pathways.Leukemia accepted article preview online, 5 October 2012; doi:10.1038/leu.2012.285.
Authors:
C Shepherd; L Banerjee; C W Cheung; M R Mansour; S Jenkinson; R E Gale; A Khwaja
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-10-05
Journal Detail:
Title:  Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K     Volume:  -     ISSN:  1476-5551     ISO Abbreviation:  Leukemia     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-5     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8704895     Medline TA:  Leukemia     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Department of Haematology, University College London Cancer Institute, London, UK.
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