PTEN posttranslational inactivation and hyperactivation of the PI3K/Akt pathway sustain primary T cell leukemia viability.
Silva A, Yunes JA, Cardoso BA, Martins LR, Jotta PY, Abecasis M et al. The role of the PTEN/AKT pathway in NOTCH1-induced leukemia. Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Palomero T, Sulis ML, Cortina M, Real PJ, Barnes K, Ciofani M et al. T-cell acute lymphoblastic leukaemia: recent molecular biology findings. Kraszewska MD, Dawidowska M, Szczepanski T, Witt M. Targeting phosphoinositide 3-kinase: moving towards therapy. Marone R, Cmiljanovic V, Giese B, Wymann MP. PI3K inhibitors for cancer treatment: where do we stand? Biochem Soc Trans 2009 37: 265–272.
Maira SM, Stauffer F, Schnell C, Garcia-Echeverria C. Take your PIK: phosphatidylinositol 3-kinase inhibitors race through the clinic and toward cancer therapy. mTOR: from growth signal integration to cancer, diabetes and ageing. Progress in the preclinical discovery and clinical development of class I and dual class I/IV phosphoinositide 3-kinase (PI3K) inhibitors. Shuttleworth SJ, Silva FA, Cecil AR, Tomassi CD, Hill TJ, Raynaud FI et al. 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. 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. Microarray studies showed a global increase in NOTCH target gene expression upon PI3K/mTOR inhibition. 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. Commitment to cell death occurred within 48–72 h and was maximal when PI3K, mTOR and NOTCH activities were inhibited. 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. 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.
PI3K, mTOR and NOTCH pathways are frequently dysregulated in T-cell acute lymphoblastic leukaemia (T-ALL).
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