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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Apoptosis / drug effects*
-
Biomarkers, Tumor / genetics
-
Biomarkers, Tumor / metabolism
-
Blotting, Western
-
Cell Cycle / drug effects
-
Cell Proliferation / drug effects
-
Furans / pharmacology
-
Gene Expression Profiling
-
Humans
-
Oligonucleotide Array Sequence Analysis
-
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
-
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / metabolism
-
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / pathology*
-
Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
-
Proto-Oncogene Proteins c-akt / genetics
-
Proto-Oncogene Proteins c-akt / metabolism
-
Proto-Oncogene Proteins c-myc / genetics
-
Proto-Oncogene Proteins c-myc / metabolism*
-
Pyridines / pharmacology
-
Pyrimidines / pharmacology
-
RNA, Messenger / genetics
-
Real-Time Polymerase Chain Reaction
-
Receptors, Notch / antagonists & inhibitors
-
Receptors, Notch / genetics
-
Receptors, Notch / metabolism*
-
Reverse Transcriptase Polymerase Chain Reaction
-
Signal Transduction / drug effects*
-
TOR Serine-Threonine Kinases / antagonists & inhibitors*
-
TOR Serine-Threonine Kinases / genetics
-
TOR Serine-Threonine Kinases / metabolism
-
Tumor Cells, Cultured
-
Up-Regulation
Substances
-
Biomarkers, Tumor
-
Furans
-
MYC protein, human
-
PI103
-
Proto-Oncogene Proteins c-myc
-
Pyridines
-
Pyrimidines
-
RNA, Messenger
-
Receptors, Notch
-
MTOR protein, human
-
Proto-Oncogene Proteins c-akt
-
TOR Serine-Threonine Kinases