A protein that appears on the surface of small-cell lung cancer cells, now hit by a drug that pulls T cells onto them. This dossier gathers the 2 products (1 approved), 2 trials, 4 pathways and 1 resistance route in the corpus that involve it, with external identifiers so it can be joined to UniProt, ChEMBL, Open Targets and the rest of biology.
Biology
Normally intracellular Golgi protein; ASCL1-driven neuroendocrine lineage exposes it on the membrane.
- Small-cell lung cancer
- Neuroendocrine prostate cancer
- Large-cell neuroendocrine carcinoma
Elsewhere: identifiers and databases
Built from HGNC, Ensembl, UniProt and ChEMBL idsHow common it is, by cancer
Full matrix →| Cancer | Prevalence | Measure | Note | Source |
|---|---|---|---|---|
| Small-cell lung cancer | 80-85% | IHC, any expression | Wikipedia | |
| Prostate cancer | 70-80% | Neuroendocrine prostate cancer only | Rare in adenocarcinoma | Wikipedia |
Approximate, population-level figures; the measure column says what was counted. Ranges show the midpoint as a bar.
Products by modality and phase
Browse products →| Modality | Approved | Withdrawn or failed |
|---|---|---|
| ADC 1 | — | |
| T-cell engager 1 | — |
Trials
Evidence ranking →| Trial | Phase | Status | Setting | Result | Products |
|---|---|---|---|---|---|
| DeLLphi-304 NCT05740566 | 3 | Positive | Second-line small-cell lung cancer: tarlatamab vs chemotherapy | OS HR 0.60. | |
| DeLLphi-305 NCT06211036 | 3 | Recruiting | First-line maintenance in ES-SCLC after platinum-etoposide-durvalumab: tarlatamab + durvalumab vs durvalumab |
Resistance routes that involve this target
Unaddressed routes →RB1/TP53 loss enables transdifferentiation; AR-indifferent, DLL3-positive, PSMA-negative.
- Platinum-etoposide; DLL3 engagers (tarlatamab) and B7-H3 ADCs in trials
Pathways where it is a node
Pathway-to-drug matrix →- Cancer stem cells & phenotypic plasticityNode: Lineage switch (NE transformation) · 2 druggable nodes
Some cancer cells behave like stem cells: they can regrow the whole tumour, resist treatment, and switch identities. This plasticity explains why tumours come back and why some lung and prostate cancers transform into a different cancer type under therapy.
Which nodes have drugs → - Lineage plasticity & neuroendocrine transformationNode: DLL3, B7-H3, SEZ6 surface · 5 druggable nodes
Under pressure from a drug that blocks its identity (the androgen receptor in prostate cancer, EGFR in lung cancer), a tumour can change what kind of cell it is, becoming a small-cell neuroendocrine cancer that no longer needs the blocked signal. It is the ultimate escape: not a new mutation in the engine, but a new engine.
Which nodes have drugs → - Notch signallingNode: DLL3 (inhibitory; SCLC surface) · 1 druggable nodes
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.
Which nodes have drugs → - Resistance routes: how a blocked pathway comes backNode: 4 Lineage switch, persisters · 6 druggable nodes
When a drug blocks a cancer's engine, the cancer has five ways back: change the part the drug binds, make more of it, take a side road, switch to a different engine altogether, or stop letting the drug in. Knowing which route a tumour took decides the next drug.
Which nodes have drugs →
Companion diagnostics and assays
Assay registry →No companion diagnostic in the registry measures this target.
Preclinical models
All models →No model entry for this target yet; check the cancer entries on the models page.
Open questions
All open questions →- 01
Does adding tarlatamab to first-line chemo-immunotherapy in small-cell lung cancer improve survival, and can DLL3 expression or subtype select patients?
clinicalindustryWhy unresolved. DeLLphi-304 proved second-line benefit; DeLLphi-305 tests first-line maintenance with durvalumab. DLL3 is not tested before treatment, yet expression varies by ASCL1 subtype and falls with plasticity.
What would answer it. DeLLphi-305 overall survival with subtype and DLL3 IHC analysed prospectively.
Source: DeLLphi-301, NEJM 2023
Ideas and companies
Key papers and the live literature
Preprints →- DeLLphi-301: tarlatamab, a DLL3-targeting T-cell engager, in previously treated small-cell lung cancer · New England Journal of Medicine 2023
Query for this target: (TITLE:"DLL3" OR ABSTRACT:"DLL3") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about DLL3, not a curated reading list.
Export
The dossier as machine-readable JSON: identifiers from HGNC, Ensembl, UniProt and ChEMBL, products with status, trials, pathways, hotspots, open questions and assays. The full entity record is in the open API at /api/v1/entities/dll3.json. Licence CC BY 4.0.