Notch signalling
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.
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 (poor prognosis); 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.
In one picture
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'.
Diagram
top- 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
Notes
top- Leading programmes: Aster (Brigham/Harvard) on Notch in leukaemia; Pear (Penn); Radtke (EPFL).