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UCSC Genome Browser Gene Interaction Graph
Gene interactions and pathways from curated databases and text-mining
Leukemia 2013, PMID: 23038273

PI3K/mTOR inhibition upregulates NOTCH-MYC signalling leading to an impaired cytotoxic response.

Shepherd, C; Banerjee, L; Cheung, C W; Mansour, M R; Jenkinson, S; Gale, R E; Khwaja, A

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 γ-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/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 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.

Diseases/Pathways annotated by Medline MESH: Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Document information provided by NCBI PubMed

Text Mining Data

NOTCH-MYC ⊣ PI3K/mTOR: " PI3K/mTOR inhibition upregulates NOTCH-MYC signalling leading to an impaired cytotoxic response "

NOTCH-MYC ⊣ PI3K/mTOR: " PI3K/mTOR inhibition upregulates NOTCH-MYC signalling leading to an impaired cytotoxic response "

NOTCH-MYC ⊣ PI3K/mTOR: " PI3K/mTOR inhibition upregulates NOTCH-MYC signalling leading to an impaired cytotoxic response "

NOTCH-MYC ⊣ PI3K/mTOR: " PI3K/mTOR inhibition upregulates NOTCH-MYC signalling leading to an impaired cytotoxic response "

Manually curated Databases

No curated data.