# DLL3

Source: https://onco.cc/targets/dll3/  
OnCo record `dll3` (Target). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

A protein that appears on the surface of small-cell lung cancer cells, now hit by a drug that pulls T cells onto them.

## Summary

Delta-like ligand 3 is an inhibitory Notch ligand aberrantly surface-expressed in ~85% of small-cell lung cancer and neuroendocrine prostate cancer. The first DLL3 ADC (rovalpituzumab tesirine) failed; the T-cell engager tarlatamab (Imdelltra) succeeded, with a survival benefit in second-line SCLC (DeLLphi-304). Trispecifics and CAR-T follow.

## Fields

- Kind: Target
- Last checked: 2026-09-04
- Tags: t-cell-engager-target
- Symbol: DLL3
- Class: surface-antigen
- Biology: Normally intracellular Golgi protein; ASCL1-driven neuroendocrine lineage exposes it on the membrane.
- Where found: Small-cell lung cancer; Neuroendocrine prostate cancer; Large-cell neuroendocrine carcinoma

## Notes

- Small-cell lung cancer: DLL3 is an inhibitory NOTCH ligand switched on downstream of ASCL1, which is why its expression follows the subtype rather than being uniform: the ASCL1-dominant and NEUROD1-dominant tumours are DLL3 high, and the POU2F3 and double-negative tumours are DLL3 low (Baine 2020). A DLL3-directed medicine is therefore aimed at roughly the 86% of tumours that are neuroendocrine-high, not at the whole disease.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/DLL3
- Wikipedia: https://en.wikipedia.org/wiki/DLL3

## Connected records

- biomarkers: [DLL3 expression](https://onco.cc/biomarkers/dll3-expression/)
- cancers: [Extensive-stage small-cell lung cancer](https://onco.cc/cancers/extensive-stage-sclc/), [Extrapulmonary neuroendocrine carcinoma](https://onco.cc/cancers/extrapulmonary-nec/), [Limited-stage small-cell lung cancer](https://onco.cc/cancers/limited-stage-sclc/), [Lung cancer (all types)](https://onco.cc/cancers/lung-cancer/), [Neuroendocrine and small-cell prostate cancer](https://onco.cc/cancers/prostate-nepc/), [Neuroendocrine tumours](https://onco.cc/cancers/neuroendocrine/), [Prostate cancer](https://onco.cc/cancers/prostate/), [Small-cell lung cancer](https://onco.cc/cancers/sclc/)
- drugs: [DJI136](https://onco.cc/drugs/dji136/), [Obrixtamig](https://onco.cc/drugs/obrixtamig/), [Peluntamig](https://onco.cc/drugs/peluntamig/), [Rovalpituzumab tesirine](https://onco.cc/drugs/rovalpituzumab-tesirine/), [Tarlatamab](https://onco.cc/drugs/tarlatamab/), [ZL-1310](https://onco.cc/drugs/zl-1310/)
- companies: [Abdera Therapeutics](https://onco.cc/companies/abdera-therapeutics/), [Harpoon Therapeutics](https://onco.cc/companies/harpoon-therapeutics/), [IDEAYA Biosciences](https://onco.cc/companies/ideaya-biosciences/)
- pathways: [Cancer stem cells & phenotypic plasticity](https://onco.cc/pathways/cancer-stem-cells-plasticity/), [Lineage plasticity & neuroendocrine transformation](https://onco.cc/pathways/lineage-plasticity-neuroendocrine/), [Notch signalling](https://onco.cc/pathways/notch/), [Resistance routes: how a blocked pathway comes back](https://onco.cc/pathways/resistance-routes-map/)
- trials: [Adaptive Phase 1/2 Study of Dual-Target CAR-NK Cells in Relapsed/Refractory Small Cell Lung Cancer (SCLC)](https://onco.cc/trials/nct07744256/), [Adaptive Phase 1/2 Study of Dual-Target CAR-NK Cells in Relapsed/Refractory Small Cell Lung Cancer (SCLC)](https://onco.cc/trials/nct07480213/), [DeLLphi-304](https://onco.cc/trials/dellphi-304/), [DeLLphi-305](https://onco.cc/trials/dellphi-305/)
- pairings: [Sequencing DLL3 engager and B7-H3 ADC in relapsed SCLC](https://onco.cc/pairings/tarlatamab-vs-idxd-sequence/)
- ideas: [Detect tumours changing cell type from RNA in the blood](https://onco.cc/ideas/idea-bio1-cfrna-plasticity-tracking/), [Run small-cell lung cancer as one platform with shared controls and subtype stratification](https://onco.cc/ideas/idea-lung-small-cell-platform-with-shared-controls-and-subtypes/), [Subtype-directed therapy for SCLC (ASCL1 / NEUROD1 / POU2F3 / inflamed)](https://onco.cc/ideas/idea-sclc-subtype-directed/)
- key papers: [Comprehensive genomic profiles of small cell lung cancer](https://onco.cc/key-papers/paper-george-sclc-genomic-profiles-nature-2015/), [DeLLphi-301: tarlatamab, a DLL3-targeting T-cell engager, in previously treated small-cell lung cancer](https://onco.cc/key-papers/paper-dellphi-301-nejm-2023/), [Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data](https://onco.cc/key-papers/paper-rudin-sclc-molecular-subtypes-nat-rev-cancer-2019/), [Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities](https://onco.cc/key-papers/paper-gay-sclc-subtypes-inflamed-cancer-cell-2021/), [SCLC subtypes defined by ASCL1, NEUROD1, POU2F3, and YAP1: a comprehensive immunohistochemical and histopathologic characterization](https://onco.cc/key-papers/paper-baine-sclc-subtype-immunohistochemistry-jto-2020/)
- technologies: [Radio-antibody & radio-ADC](https://onco.cc/technologies/radioimmunotherapy/), [T-cell engagers (bispecific)](https://onco.cc/technologies/t-cell-engager/)
- people: [Charles M. Rudin](https://onco.cc/people/charles-rudin/)
- bottlenecks: [Cold tumours and the immunosuppressive microenvironment](https://onco.cc/bottlenecks/b-tme-immunosuppression/)
- terms: [Cancer stem cell theory and phenotypic plasticity](https://onco.cc/terms/cancer-stem-cell-theory/), [Hallmark (2022): unlocking phenotypic plasticity](https://onco.cc/terms/unlocking-phenotypic-plasticity/), [Small-cell lung cancer transcription-factor subtypes (SCLC-A, SCLC-N, SCLC-P, SCLC-I) and SLFN11](https://onco.cc/terms/sclc-molecular-subtypes/)
- institutions: [Hospital Universitario 12 de Octubre](https://onco.cc/institutions/12-de-octubre/)

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JSON: https://onco.cc/api/v1/entities/dll3.json