ArticleLeukemia2013
PI3K/mTOR inhibition upregulates NOTCH-MYC signalling leading to an impaired cytotoxic response.
Article in Leukemia, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
44 citing papers in PubMed, 73 citations in OpenAlex.
- Insulin receptor substrate 2 (IRS2) confers resistance to PI3K pathway inhibition in PIK3CA mutant breast cancer.The Journal of biological chemistry · 2026Article
- The mitochondria as an emerging target of self-renewal in T-cell acute lymphoblastic leukemia.Cancer biology & therapy · 2025Review
- Promising Drugs Targeting Specific Mechanisms of Deregulation in T Cell Lineage Acute Lymphoblastic Leukemia.Oncology and therapy · 2025Review
- Preclinical development of anti-CD21 chimeric antigen receptor T cells to treat T cell acute lymphoblastic leukemia.Science translational medicine · 2025Article
- Genome-wide CRISPR screen identifies IRF1 and TFAP4 as transcriptional regulators of Galectin-9 in T cell acute lymphoblastic leukemia.Science advances · 2025Article
- Notch and Hedgehog Signaling Unveiled: Crosstalk, Roles, and Breakthroughs in Cancer Stem Cell Research.Life (Basel, Switzerland) · 2025Review
- MYC is a clinically significant driver of mTOR inhibitor resistance in breast cancer.The Journal of experimental medicine · 2023Article
- Decoding of translation-regulating entities reveals heterogeneous translation deficiency patterns in cellular senescence.Aging cell · 2023Article
- Targeting Leukemia-Initiating Cells and Leukemic Niches: The Next Therapy Station for T-Cell Acute Lymphoblastic Leukemia?Cancers · 2022Review
- MYC and therapy resistance in cancer: risks and opportunities.Molecular oncology · 2022Review
- mTOR: A Potential New Target in Nonalcoholic Fatty Liver Disease.International journal of molecular sciences · 2022Review
- A Phase I Study Investigating AZD8186, a Potent and Selective Inhibitor of PI3Kβ/δ, in Patients with Advanced Solid Tumors.Clinical cancer research : an official journal of the American Association for Cancer Research · 2022Article
- Current state of CAR-T therapy for T-cell malignancies.Therapeutic advances in hematology · 2022Review
- A Synopsis of Signaling Crosstalk of Pericytes and Endothelial Cells in Salivary Gland.Dentistry journal · 2021Review
- NOTCH3-targeted antibody drug conjugates regress tumors by inducing apoptosis in receptor cells and through transendocytosis into ligand cells.Cell reports. Medicine · 2021Article
- Notch1 signaling pathway promotes invasion, self-renewal and growth of glioma initiating cells via modulating chemokine system CXCL12/CXCR4.Journal of experimental & clinical cancer research : CR · 2019Article
- Notch and mTOR Signaling Pathways Promote Human Gastric Cancer Cell Proliferation.Neoplasia (New York, N.Y.) · 2019Article
- Targeting mTOR in Acute Lymphoblastic Leukemia.Cells · 2019Review
- Memantine potentiates cytarabine-induced cell death of acute leukemia correlating with inhibition of KCell communication and signaling : CCS · 2019Article
- Therapeutic Targeting of mTOR in T-Cell Acute Lymphoblastic Leukemia: An Update.International journal of molecular sciences · 2018Review
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.