{"entity":{"id":"gamma-secretase","kind":"target","name":"Gamma-secretase (PSEN1)","aka":[],"tldr":"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.","asOf":"2026-09-04","wikipedia":"https://en.wikipedia.org/wiki/Gamma_secretase","links":[{"label":"UniProt P49768: PSEN1","url":"https://www.uniprot.org/uniprotkb/P49768/entry"}],"tags":[],"related":[],"cancers":["desmoid-tumour"],"sections":[],"technologies":["gamma-secretase-inhibitors"],"targets":[],"drugs":["nirogacestat"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"symbol":"PSEN1","role":[],"sources":[],"specificity":"broadly-expressed","distribution":"one-type","specificityNote":"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.)","specificitySources":[{"label":"Human Protein Atlas PSEN1 tissue","url":"https://www.proteinatlas.org/ENSG00000080815-PSEN1/tissue","note":"RNA tissue and blood lineage specificity, normal tissue antibody staining (version 25.1, CC BY-SA 3.0)"},{"label":"Open Targets ENSG00000080815 associations","url":"https://platform.opentargets.org/target/ENSG00000080815/associations","note":"cancer associations at or above 0.5 (CC0)"}],"hgnc":"HGNC:9508","ensembl":"ENSG00000080815","uniprot":"P49768","entrez":"5663","firstDescribed":1995,"firstDescribedBasis":"sequence","firstDescribedNote":"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\".","firstDescribedSource":"https://pubmed.ncbi.nlm.nih.gov/7596406/","biology":"Intramembrane aspartyl protease complex (PSEN1 or PSEN2, nicastrin, APH1, PEN2) that releases the Notch intracellular domain.","whereFound":["Desmoid tumours","Investigational in T-cell acute lymphoblastic leukaemia and as a BCMA-boosting partner in myeloma"],"targetClass":"enzyme","prevalence":[{"cancerId":"desmoid-tumour","pct":"about 85","measure":"CTNNB1 mutation in sporadic desmoid tumours, the Wnt activation that Notch inhibition addresses","source":"https://doi.org/10.2353/ajpath.2008.080475"}]},"route":"/targets/gamma-secretase/","neighbours":{"cancer":[{"id":"desmoid-tumour","kind":"cancer","name":"Desmoid tumour","route":"/cancers/desmoid-tumour/"}],"technology":[{"id":"gamma-secretase-inhibitors","kind":"technology","name":"Gamma-secretase inhibitors","route":"/technologies/gamma-secretase-inhibitors/"}],"drug":[{"id":"nirogacestat","kind":"drug","name":"Nirogacestat","route":"/drugs/nirogacestat/"}],"paper":[{"id":"paper-stoeck-notch-rearrangements-tnbc-cancer-discov-2014","kind":"paper","name":"Discovery of biomarkers predictive of GSI response in triple-negative breast cancer and adenoid cystic carcinoma","route":"/key-papers/paper-stoeck-notch-rearrangements-tnbc-cancer-discov-2014/"},{"id":"paper-wang-notch-pest-mutations-tnbc-ccr-2015","kind":"paper","name":"PEST domain mutations in Notch receptors comprise an oncogenic driver segment in triple-negative breast cancer sensitive to a gamma-secretase inhibitor","route":"/key-papers/paper-wang-notch-pest-mutations-tnbc-ccr-2015/"}],"company":[{"id":"immunome","kind":"company","name":"Immunome","route":"/companies/immunome/"}]}}