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Oncogenes, Fusion Genes and Tumor Suppressor Genes

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

Leukemia volume 27, pages 650–660 (2013)Cite this article

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Abstract

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.

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Acknowledgements

This work was undertaken at the UCLH/UCL which received a proportion of funding from the NIHR Biomedical Research Centres funding scheme of the UK Department of Health. The work was supported by Leukaemia and Lymphoma Research, UK (LB and CWC), The Kay Kendall Leukaemia Fund (CS), the Medical Research Council UK (MRM) and the Tapner ALL Research Fund.

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  1. C Shepherd and L Banerjee: These two authors contributed equally to this study.

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  1. Department of Haematology, UCL Cancer Institute, University College London, London, UK

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

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  1. C Shepherd
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Correspondence to A Khwaja.

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Shepherd, C., Banerjee, L., Cheung, C. et al. PI3K/mTOR inhibition upregulates NOTCH-MYC signalling leading to an impaired cytotoxic response. Leukemia 27, 650–660 (2013). https://doi.org/10.1038/leu.2012.285

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