title: PI3K/mTOR inhibition upregulates NOTCH-MYC signalling leading to an impaired cytotoxic response.
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.
authors.affiliation: Department of Haematology, University College, London, UK.
authors.forename: C
authors.initials: C
authors.lastname: Shepherd
authors.forename: L
authors.initials: L
authors.lastname: Banerjee
authors.forename: C W
authors.initials: CW
authors.lastname: Cheung
authors.forename: M R
authors.initials: MR
authors.lastname: Mansour
authors.forename: S
authors.initials: S
authors.lastname: Jenkinson
authors.forename: R E
authors.initials: RE
authors.lastname: Gale
authors.forename: A
authors.initials: A
authors.lastname: Khwaja
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005663:Furans / Q000494:pharmacology; D020869:Gene Expression Profiling; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; D005663:Furans; C489427:MYC protein, human; C522973:PI103; D016271:Proto-Oncogene Proteins c-myc; D011725:Pyridines; D011743:Pyrimidines; D012333:RNA, Messenger; D051880:Receptors, Notch; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases