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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 (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.
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'.
It is the reality check on the subtype model and it has a direct consequence for treatment: the DLL3-directed medicines are aimed at the neuroendocrine-high subtypes, and the POU2F3 and double-negative tumours will not express the target.
One pathway page on OnCo cites this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing page listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand.
With Moffitt's classical and basal-like split (the squamous and basal-like groups overlap) this fixed the molecular vocabulary of the disease and gave Precision-Panc and the UK's Glasgow group their trial framework.
Why small-cell lung cancer has no targeted therapy in the conventional sense: it is built from the loss of TP53 and RB1, and the drugs that transformed non-small-cell disease inhibit gains rather than restore losses. The NOTCH result pointed at DLL3 and, eventually, at tarlatamab.
Carrying a cancer mutation is normal; most mutant clones never become cancer. This means blood or tissue tests that look for driver mutations alone will produce false positives, and that the question of what tips a mutant clone into cancer (tissue environment, further hits, immune surveillance) is as important as the mutation itself.
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.
Shares Abramson Cancer Center, University of Pennsylvania, MYC, MYC and the tag mechanism.
Shares Genomic analyses identify molecular subtypes of pancreatic cancer, Cancer stem cells & phenotypic plasticity, Dana-Farber Brigham Cancer Center, Non-small-cell lung cancer and the tag mechanism.
Shares Martincorena: normal sun-exposed skin is a patchwork of cancer-mutation clones, NOTCH1, Head and neck squamous cell carcinoma, Non-small-cell lung cancer and the tag mechanism.
Shares Abramson Cancer Center, University of Pennsylvania, MYC, MYC and the tag mechanism.
Shares MYC, MYC, Dana-Farber Brigham Cancer Center and the tag mechanism.
Shares MYC, Dana-Farber Brigham Cancer Center, Chronic lymphocytic leukaemia and the tag mechanism.
Shares Comprehensive genomic profiles of small cell lung cancer, MYC, Non-small-cell lung cancer and the tag mechanism.