ArticleEMBO molecular medicine2017
γ-Secretase inhibitors in cancer clinical trials are pharmacologically and functionally distinct.
Article in EMBO molecular medicine, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 90 papers, 1 of them a synthesis that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
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
90 citing papers in PubMed, 1 synthesis or guideline pooled it, 129 citations in OpenAlex.
- Pooled it
- NOTCH1 reverses immune suppression in small cell lung cancer through reactivation of STING.The Journal of clinical investigation · 2025Trial
- Translational insights and clinical challenges of targeting cancer stem cells.Signal transduction and targeted therapy · 2026Review
- Inhibition of Colorectal Cancer Cell Progression by Picroside II Through Modulation of the Notch1 Signaling Pathway.Journal of biochemical and molecular toxicology · 2026Article
- NOTCH1 intracellular domain stabilization by MDM2 plays a major role in NSCLC response to platinum.EMBO molecular medicine · 2026Article
- Intravenous administration of blood-brain barrier-crossing conjugates facilitate biomacromolecule transport into central nervous system.Nature biotechnology · 2025Article
- Protein Marker-Dependent Drug Discovery Targeting Breast Cancer Stem Cells.International journal of molecular sciences · 2025Review
- Review
- Notch Inhibitors and BH3 Mimetics in T-Cell Acute Lymphoblastic Leukemia.International journal of molecular sciences · 2024Review
- Surface Modification of Mesoporous Silica Nanoparticles as a Means to Introduce Inherent Cancer-Targeting Ability in a 3D Tumor Microenvironment.Small science · 2024Article
- Blockade of Notch1 Signaling Alleviated Podocyte Injury in Lupus Nephritis Via Inhibition of NLRP3 Inflammasome Activation.Inflammation · 2024Article
- In vitro antineoplastic effects of MK0752 in HPV-positive head and neck squamous cell carcinoma.Journal of cancer research and clinical oncology · 2023Article
- Modulation of Notch Signaling by Small-Molecular Compounds and Its Potential in Anticancer Studies.Cancers · 2023Review
- Notch signaling regulates a metabolic switch through inhibiting PGC-1α and mitochondrial biogenesis in dedifferentiated liposarcoma.Oncogene · 2023Article
- lncRNAProceedings of the National Academy of Sciences of the United States of America · 2023Article
- Targeting the DLL/Notch Signaling Pathway in Cancer: Challenges and Advances in Clinical Development.Molecular cancer therapeutics · 2023Review
- Sulindac sulfide as a non-immune suppressive γ-secretase modulator to target triple-negative breast cancer.Frontiers in immunology · 2023Article
- Notch signaling pathway: a comprehensive prognostic and gene expression profile analysis in breast cancer.BMC cancer · 2022Article
- MicroRNA Expression Variation in Female Dog (Animals : an open access journal from MDPI · 2022Article
- Engineering receptors in the secretory pathway for orthogonal signalling control.Nature communications · 2022Article
30 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
10 authors at 3 institutions in 1 country.
Funding
Abstract
γ-Secretase inhibitors (GSIs) are being actively repurposed as cancer therapeutics based on the premise that inhibition of NOTCH1 signaling in select cancers is therapeutic. Using novel assays to probe effects of GSIs against a broader panel of substrates, we demonstrate that clinical GSIs are pharmacologically distinct. GSIs show differential profiles of inhibition of the various NOTCH substrates, with some enhancing cleavage of other NOTCH substrates at concentrations where NOTCH1 cleavage is inhibited. Several GSIs are also potent inhibitors of select signal peptide peptidase (SPP/SPPL) family members. Extending these findings to mammosphere inhibition assays in triple-negative breast cancer lines, we establish that these GSIs have different functional effects. We also demonstrate that the processive γ-secretase cleavage pattern established for amyloid precursor protein (APP) occurs in multiple substrates and that potentiation of γ-secretase cleavage is attributable to a direct action of low concentrations of GSIs on γ-secretase. Such data definitively demonstrate that the clinical GSIs are not biological equivalents, and provide an important framework to evaluate results from ongoing and completed human trials with these compounds.
Indexed as
Identifiers
What OpenQuestion holds
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.