{"entity":{"id":"notch","kind":"pathway","name":"Notch signalling","aka":[],"tldr":"A cell-to-cell contact signal that decides cell fate. It drives T-cell leukaemia when mutated on, acts as a tumour suppressor in some squamous cancers when lost, and its ligand DLL3 became a drug target in small-cell lung cancer.","summary":"Notch receptors are cleaved by γ-secretase on ligand binding (Delta-like, Jagged), releasing NICD to activate HES/HEY genes. Activating NOTCH1 mutations occur in >50% of T-ALL and in CLL (shorter survival); inactivating mutations in head and neck, oesophageal, and cutaneous squamous carcinomas mark a tumour-suppressor role. γ-secretase inhibitors failed as anticancer drugs (gut toxicity) but nirogacestat is approved in desmoid tumours (2023). DLL3, an inhibitory Notch ligand aberrantly on SCLC cell surfaces, is targeted by tarlatamab. Context dependence is the central lesson.","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/Notch_signaling_pathway","links":[{"label":"Aster, Pear & Blacklow, The varied roles of Notch in cancer (Annual Review of Pathology 2017)","url":"https://doi.org/10.1146/annurev-pathol-052016-100127"}],"tags":["mechanism"],"related":[],"cancers":["sclc","all-leukemia","cll","head-and-neck","tnbc"],"sections":[],"technologies":[],"targets":["dll3"],"drugs":["tarlatamab","nirogacestat"],"companies":[],"institutions":["dana-farber","penn-abramson"],"pathways":["cancer-stem-cells-plasticity","myc"],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-aster-annu-rev-pathol"],"journals":[],"dependsOn":[],"notes":["Leading programmes: Aster (Brigham/Harvard) on Notch in leukaemia; Pear (Penn); Radtke (EPFL)."],"analogy":"A doorbell that only works when a neighbour presses it. In some cancers the bell rings constantly (T-ALL); in others it has been ripped out so cells never hear 'stop and mature'.","nodes":[{"id":"lig","label":"DLL/JAG ligand (neighbour)","x":15,"y":40},{"id":"notch","label":"NOTCH receptor","x":40,"y":40},{"id":"gs","label":"γ-secretase cleavage","x":60,"y":40},{"id":"nicd","label":"NICD → RBPJ","x":80,"y":40},{"id":"hes","label":"HES1/HEY, MYC","x":80,"y":78},{"id":"dll3","label":"DLL3 (inhibitory; SCLC surface)","x":15,"y":80,"targetId":"dll3"}],"edges":[{"from":"lig","to":"notch","type":"activates"},{"from":"notch","to":"gs","type":"activates"},{"from":"gs","to":"nicd","type":"activates"},{"from":"nicd","to":"hes","type":"activates"},{"from":"dll3","to":"notch","type":"inhibits"}],"interventions":["Nirogacestat (γ-secretase inhibitor) in desmoid tumours","DLL3-directed tarlatamab in SCLC; DLL3 ADCs and trispecifics","NOTCH1-mutant CLL: reduced benefit from anti-CD20, informs regimen choice"]},"route":"/pathways/notch/","neighbours":{"cancer":[{"id":"all-leukemia","kind":"cancer","name":"Acute lymphoblastic leukaemia","route":"/cancers/all-leukemia/"},{"id":"cll","kind":"cancer","name":"Chronic lymphocytic leukaemia","route":"/cancers/cll/"},{"id":"desmoid-tumour","kind":"cancer","name":"Desmoid tumour","route":"/cancers/desmoid-tumour/"},{"id":"head-and-neck","kind":"cancer","name":"Head and neck squamous cell carcinoma","route":"/cancers/head-and-neck/"},{"id":"marginal-zone-lymphoma","kind":"cancer","name":"Marginal zone lymphoma","route":"/cancers/marginal-zone-lymphoma/"},{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"},{"id":"sclc","kind":"cancer","name":"Small-cell lung cancer","route":"/cancers/sclc/"},{"id":"tnbc","kind":"cancer","name":"Triple-negative breast cancer (TNBC)","route":"/cancers/tnbc/"}],"target":[{"id":"dll3","kind":"target","name":"DLL3","route":"/targets/dll3/"},{"id":"myc-gene","kind":"target","name":"MYC","route":"/targets/myc-gene/"},{"id":"notch1","kind":"target","name":"NOTCH1","route":"/targets/notch1/"},{"id":"rbpj","kind":"target","name":"RBPJ","route":"/targets/rbpj/"}],"drug":[{"id":"nirogacestat","kind":"drug","name":"Nirogacestat","route":"/drugs/nirogacestat/"},{"id":"tarlatamab","kind":"drug","name":"Tarlatamab","route":"/drugs/tarlatamab/"}],"institution":[{"id":"penn-abramson","kind":"institution","name":"Abramson Cancer Center, University of Pennsylvania","route":"/institutions/penn-abramson/"},{"id":"dana-farber","kind":"institution","name":"Dana-Farber Brigham Cancer Center","route":"/institutions/dana-farber/"}],"pathway":[{"id":"cancer-stem-cells-plasticity","kind":"pathway","name":"Cancer stem cells & phenotypic plasticity","route":"/pathways/cancer-stem-cells-plasticity/"},{"id":"hedgehog","kind":"pathway","name":"Hedgehog signalling","route":"/pathways/hedgehog/"},{"id":"lineage-plasticity-neuroendocrine","kind":"pathway","name":"Lineage plasticity & neuroendocrine transformation","route":"/pathways/lineage-plasticity-neuroendocrine/"},{"id":"myc","kind":"pathway","name":"MYC","route":"/pathways/myc/"}],"paper":[{"id":"paper-george-sclc-genomic-profiles-nature-2015","kind":"paper","name":"Comprehensive genomic profiles of small cell lung cancer","route":"/key-papers/paper-george-sclc-genomic-profiles-nature-2015/"},{"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-bailey-molecular-subtypes-pancreatic-nature-2016","kind":"paper","name":"Genomic analyses identify molecular subtypes of pancreatic cancer","route":"/key-papers/paper-bailey-molecular-subtypes-pancreatic-nature-2016/"},{"id":"paper-martincorena-somatic-mutations-normal-skin-science-2015","kind":"paper","name":"Martincorena: normal sun-exposed skin is a patchwork of cancer-mutation clones","route":"/key-papers/paper-martincorena-somatic-mutations-normal-skin-science-2015/"},{"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/"},{"id":"paper-baine-sclc-subtype-immunohistochemistry-jto-2020","kind":"paper","name":"SCLC subtypes defined by ASCL1, NEUROD1, POU2F3, and YAP1: a comprehensive immunohistochemical and histopathologic characterization","route":"/key-papers/paper-baine-sclc-subtype-immunohistochemistry-jto-2020/"},{"id":"paper-aster-annu-rev-pathol","kind":"paper","name":"The Varied Roles of Notch in Cancer","route":"/key-papers/paper-aster-annu-rev-pathol/"}],"term":[{"id":"cancer-stem-cell-theory","kind":"term","name":"Cancer stem cell theory and phenotypic plasticity","route":"/terms/cancer-stem-cell-theory/"}]}}