# Gamma-secretase (PSEN1)

Source: https://onco.cc/targets/gamma-secretase/  
OnCo record `gamma-secretase` (Target). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Summary

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.

## Fields

- Kind: Target
- Last checked: 2026-09-04
- Symbol: PSEN1
- Class: enzyme
- Biology: Intramembrane aspartyl protease complex (PSEN1 or PSEN2, nicastrin, APH1, PEN2) that releases the Notch intracellular domain.
- Where found: Desmoid tumours; Investigational in T-cell acute lymphoblastic leukaemia and as a BCMA-boosting partner in myeloma

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Gamma_secretase
- UniProt P49768: PSEN1: https://www.uniprot.org/uniprotkb/P49768/entry

## Connected records

- cancers: [Desmoid tumour](https://onco.cc/cancers/desmoid-tumour/)
- technologies: [Gamma-secretase inhibitors](https://onco.cc/technologies/gamma-secretase-inhibitors/)
- drugs: [Nirogacestat](https://onco.cc/drugs/nirogacestat/)
- key papers: [Discovery of biomarkers predictive of GSI response in triple-negative breast cancer and adenoid cystic carcinoma](https://onco.cc/key-papers/paper-stoeck-notch-rearrangements-tnbc-cancer-discov-2014/), [PEST domain mutations in Notch receptors comprise an oncogenic driver segment in triple-negative breast cancer sensitive to a gamma-secretase inhibitor](https://onco.cc/key-papers/paper-wang-notch-pest-mutations-tnbc-ccr-2015/)
- companies: [Immunome](https://onco.cc/companies/immunome/)

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