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The membrane enzyme that releases the active part of Notch. Nirogacestat blocks it and became the first drug approved for desmoid tumours, the aggressive but non-metastasising growths driven by Wnt signalling.
Gamma-secretase is a four-protein complex whose catalytic core, presenilin 1, cleaves membrane proteins including Notch receptors and amyloid precursor protein. Cleaving Notch releases its intracellular domain, so blocking gamma-secretase shuts down Notch signalling, which desmoid tumours depend on alongside their Wnt pathway mutations. Nirogacestat, approved in 2023 after the DeFi trial, shrinks desmoid tumours and reduces pain, at the cost of diarrhoea and ovarian toxicity in women. Earlier gamma-secretase inhibitors failed in Alzheimer disease and in T-cell leukaemia because of gut toxicity, and the same class is now used to unmask BCMA on myeloma cells to improve BCMA-directed therapy.
In plain words · The membrane enzyme that releases the active part of Notch. Nirogacestat blocks it and became the first drug approved for desmoid tumours, the aggressive but non-metastasising growths driven by Wnt signalling.
The membrane enzyme that releases the active part of Notch. Nirogacestat blocks it and became the first drug approved for desmoid tumours, the aggressive but non-metastasising growths driven by Wnt signalling.
Intramembrane aspartyl protease complex (PSEN1 or PSEN2, nicastrin, APH1, PEN2) that releases the Notch intracellular domain.
No product in this corpus aims at Gamma-secretase (PSEN1) yet. Inhibitors are shaped to fit the enzyme's active site so the reaction the cancer relies on stops.
Broadly expressed or essential: HPA finds the RNA at low tissue specificity; the 1 medicine aimed at it (Nirogacestat) act on the wild-type protein, so normal tissue is exposed and the therapeutic window comes from the tumour's faster division or its dependence on the protein. HPA PSEN1: RNA low tissue specificity; high antibody staining in 14 normal tissues; highest cancer staining stomach cancer (6 of 12 high). Distribution: 1 cancer family in the corpus carries a prevalence row, label threshold or catalogue link for it (Sarcomas (soft tissue, bone, GIST)); Open Targets associates it with 1 specific cancer type at or above 0.5 (desmoid tumor). (Rule 7 of scripts/fetch-target-specificity.ts.)
Sources: Human Protein Atlas PSEN1 tissue; Open Targets ENSG00000080815 associations
First described 1995. Earliest sequence paper UniProt cites for the protein: Sherrington et al, Nature, 1995, "Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease". Source.
Intramembrane aspartyl protease complex (PSEN1 or PSEN2, nicastrin, APH1, PEN2) that releases the Notch intracellular domain.
RNA: low tissue specificity, detected in all normal tissues.
Medium: Adrenal gland, Appendix, Breast, Caudate, Cervix, Epididymis, Esophagus, Hippocampus.
Medium only: breast cancer, carcinoid, glioma, head and neck cancer.
Human Protein Atlas version 25.1, antibody staining at reliability approved, enhanced or supported; used under CC BY-SA 3.0. Staining counts are patients per level in the atlas cohort, not population prevalence.
| Cancer | Prevalence | Measure | Note | Source |
|---|---|---|---|---|
| Desmoid tumour | about 85% | CTNNB1 mutation in sporadic desmoid tumours, the Wnt activation that Notch inhibition addresses | doi.org |
Approximate, population-level figures; the measure column says what was counted. Ranges show the midpoint as a bar.
It widens the NOTCH driver segment beyond rearrangements to PEST mutations that ordinary DNA panels can report, the finding that fed NOTCH-mutant cohorts into basket trials.
NOTCH is a real but small driver segment in TNBC with a receptor-specific drug response, which is why NOTCH-directed trials require rearrangement or N1-ICD testing rather than treating all TNBC.
Query for this target: (TITLE:"Gamma-secretase" OR ABSTRACT:"Gamma-secretase" OR TITLE:"PSEN1" OR ABSTRACT:"PSEN1") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about Gamma-secretase (PSEN1), not a curated reading list.
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