PI3K/mTOR Inhibition Upregulates NOTCH-MYC Signalling Leading to an Impaired Cytotoxic Response

Abstract 1358 The PI3K/mTOR and NOTCH pathways are promising therapeutic targets for the treatment of T-ALL. Hyperactivation of the PI3K/mTOR pathway occurs frequently, predominantly due to loss of PTEN function through deletion, mutation, microRNA induced downregulation or post-translational modifi...

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Published in:Blood 2012-11, Vol.120 (21), p.1358-1358
Main Authors: Shepherd, Clare, Banerjee, Lalita, Cheung, Ching Wai, Mansour, Marc R, Jenkinson, Sarah, Gale, Rosemary E, Khwaja, Asim
Format: Article
Language:English
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Summary:Abstract 1358 The PI3K/mTOR and NOTCH pathways are promising therapeutic targets for the treatment of T-ALL. Hyperactivation of the PI3K/mTOR pathway occurs frequently, predominantly due to loss of PTEN function through deletion, mutation, microRNA induced downregulation or post-translational modification. NOTCH signalling is aberrantly activated in the majority of patients, most commonly due to mutation of Notch-1. Activation of NOTCH signalling can also positively regulate mTOR activity and increase PI3K/Akt signalling via downregulation of PTEN expression. We examined the effects of PI3K/mTOR blockade, using the dual inhibitor PI-103, on the proliferation and survival of T-ALL cell lines with various combinations of NOTCH and PTEN abnormalities. There was marked reduction in the proliferation of all T-ALL cell lines tested, regardless of their PTEN status or level of activated Akt. However, using Annexin-V/PI staining, we observed significant induction of cell death (
ISSN:0006-4971
1528-0020
DOI:10.1182/blood.V120.21.1358.1358