{"entity":{"id":"dll3","kind":"target","name":"DLL3","aka":[],"tldr":"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.","asOf":"2026-09-04","wikipedia":"https://en.wikipedia.org/wiki/DLL3","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/DLL3"}],"tags":["t-cell-engager-target"],"related":["dll3-expression"],"cancers":["sclc","prostate"],"sections":[],"technologies":[],"targets":[],"drugs":["zl-1310","peluntamig","dji136"],"companies":["abdera-therapeutics","harpoon-therapeutics","ideaya-biosciences"],"institutions":[],"pathways":["notch","lineage-plasticity-neuroendocrine"],"terms":[],"trials":["nct07744256","nct07480213"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"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."],"symbol":"DLL3","role":[],"sources":[],"specificity":"tumour-associated","distribution":"few-types","specificityNote":"Tumour-associated overexpression: 5 cell-killing or cell-finding medicines (ZL-1310, DJI136, Obrixtamig and more) aim at the antigen, which HPA finds with no normal tissue stained high; the medicine relies on the tumour carrying more of it than the normal tissue it shares it with. HPA DLL3: RNA tissue enriched (brain 27 nTPM); blood lineage group enriched (B-cells 3 nTPM, T-cells 1 nTPM); no normal tissue stained high. Distribution: 2 cancer families in the corpus carry a prevalence row, label threshold or catalogue link for it (Lung cancer (all types), Prostate cancer); Open Targets associates it with 1 specific cancer type at or above 0.5 (small cell lung carcinoma). (Rule 5 of scripts/fetch-target-specificity.ts.)","specificitySources":[{"label":"Human Protein Atlas DLL3 tissue","url":"https://www.proteinatlas.org/ENSG00000090932-DLL3/tissue","note":"RNA tissue and blood lineage specificity, normal tissue antibody staining (version 25.1, CC BY-SA 3.0)"},{"label":"Human Protein Atlas DLL3 pathology","url":"https://www.proteinatlas.org/ENSG00000090932-DLL3/pathology","note":"patients per staining level per cancer type (version 25.1, CC BY-SA 3.0)"},{"label":"Open Targets ENSG00000090932 associations","url":"https://platform.opentargets.org/target/ENSG00000090932/associations","note":"cancer associations at or above 0.5 (CC0)"}],"hgnc":"HGNC:2909","ensembl":"ENSG00000090932","uniprot":"Q9NYJ7","entrez":"10683","firstDescribed":2000,"firstDescribedBasis":"sequence","firstDescribedNote":"Earliest sequence paper UniProt cites for the protein: Bulman M.P. et al, Nat. Genet, 2000, \"Mutations in the human delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis\".","firstDescribedSource":"https://pubmed.ncbi.nlm.nih.gov/10742114/","biology":"Normally intracellular Golgi protein; ASCL1-driven neuroendocrine lineage exposes it on the membrane.","whereFound":["Small-cell lung cancer","Neuroendocrine prostate cancer","Large-cell neuroendocrine carcinoma"],"targetClass":"surface-antigen","prevalence":[{"cancerId":"sclc","pct":"80-85","measure":"IHC, any expression","source":"https://en.wikipedia.org/wiki/DLL3"},{"cancerId":"prostate","pct":"70-80","measure":"Neuroendocrine prostate cancer only","source":"https://en.wikipedia.org/wiki/DLL3","note":"Rare in adenocarcinoma"}]},"route":"/targets/dll3/","neighbours":{"biomarker":[{"id":"dll3-expression","kind":"biomarker","name":"DLL3 expression","route":"/biomarkers/dll3-expression/"}],"cancer":[{"id":"extensive-stage-sclc","kind":"cancer","name":"Extensive-stage small-cell lung cancer","route":"/cancers/extensive-stage-sclc/"},{"id":"extrapulmonary-nec","kind":"cancer","name":"Extrapulmonary neuroendocrine carcinoma","route":"/cancers/extrapulmonary-nec/"},{"id":"limited-stage-sclc","kind":"cancer","name":"Limited-stage small-cell lung cancer","route":"/cancers/limited-stage-sclc/"},{"id":"lung-cancer","kind":"cancer","name":"Lung cancer (all types)","route":"/cancers/lung-cancer/"},{"id":"prostate-nepc","kind":"cancer","name":"Neuroendocrine and small-cell prostate cancer","route":"/cancers/prostate-nepc/"},{"id":"neuroendocrine","kind":"cancer","name":"Neuroendocrine tumours","route":"/cancers/neuroendocrine/"},{"id":"prostate","kind":"cancer","name":"Prostate cancer","route":"/cancers/prostate/"},{"id":"sclc","kind":"cancer","name":"Small-cell lung cancer","route":"/cancers/sclc/"}],"drug":[{"id":"dji136","kind":"drug","name":"DJI136","route":"/drugs/dji136/"},{"id":"obrixtamig","kind":"drug","name":"Obrixtamig","route":"/drugs/obrixtamig/"},{"id":"peluntamig","kind":"drug","name":"Peluntamig","route":"/drugs/peluntamig/"},{"id":"rovalpituzumab-tesirine","kind":"drug","name":"Rovalpituzumab tesirine","route":"/drugs/rovalpituzumab-tesirine/"},{"id":"tarlatamab","kind":"drug","name":"Tarlatamab","route":"/drugs/tarlatamab/"},{"id":"zl-1310","kind":"drug","name":"ZL-1310","route":"/drugs/zl-1310/"}],"company":[{"id":"abdera-therapeutics","kind":"company","name":"Abdera Therapeutics","route":"/companies/abdera-therapeutics/"},{"id":"harpoon-therapeutics","kind":"company","name":"Harpoon Therapeutics","route":"/companies/harpoon-therapeutics/"},{"id":"ideaya-biosciences","kind":"company","name":"IDEAYA Biosciences","route":"/companies/ideaya-biosciences/"}],"pathway":[{"id":"cancer-stem-cells-plasticity","kind":"pathway","name":"Cancer stem cells & phenotypic plasticity","route":"/pathways/cancer-stem-cells-plasticity/"},{"id":"lineage-plasticity-neuroendocrine","kind":"pathway","name":"Lineage plasticity & neuroendocrine transformation","route":"/pathways/lineage-plasticity-neuroendocrine/"},{"id":"notch","kind":"pathway","name":"Notch signalling","route":"/pathways/notch/"},{"id":"resistance-routes-map","kind":"pathway","name":"Resistance routes: how a blocked pathway comes back","route":"/pathways/resistance-routes-map/"}],"trial":[{"id":"nct07744256","kind":"trial","name":"Adaptive Phase 1/2 Study of Dual-Target CAR-NK Cells in Relapsed/Refractory Small Cell Lung Cancer (SCLC)","route":"/trials/nct07744256/"},{"id":"nct07480213","kind":"trial","name":"Adaptive Phase 1/2 Study of Dual-Target CAR-NK Cells in Relapsed/Refractory Small Cell Lung Cancer (SCLC)","route":"/trials/nct07480213/"},{"id":"dellphi-304","kind":"trial","name":"DeLLphi-304","route":"/trials/dellphi-304/"},{"id":"dellphi-305","kind":"trial","name":"DeLLphi-305","route":"/trials/dellphi-305/"}],"pairing":[{"id":"tarlatamab-vs-idxd-sequence","kind":"pairing","name":"Sequencing DLL3 engager and B7-H3 ADC in relapsed SCLC","route":"/pairings/tarlatamab-vs-idxd-sequence/"}],"idea":[{"id":"idea-bio1-cfrna-plasticity-tracking","kind":"idea","name":"Detect tumours changing cell type from RNA in the blood","route":"/ideas/idea-bio1-cfrna-plasticity-tracking/"},{"id":"idea-lung-small-cell-platform-with-shared-controls-and-subtypes","kind":"idea","name":"Run small-cell lung cancer as one platform with shared controls and subtype stratification","route":"/ideas/idea-lung-small-cell-platform-with-shared-controls-and-subtypes/"},{"id":"idea-sclc-subtype-directed","kind":"idea","name":"Subtype-directed therapy for SCLC (ASCL1 / NEUROD1 / POU2F3 / inflamed)","route":"/ideas/idea-sclc-subtype-directed/"}],"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-dellphi-301-nejm-2023","kind":"paper","name":"DeLLphi-301: tarlatamab, a DLL3-targeting T-cell engager, in previously treated small-cell lung cancer","route":"/key-papers/paper-dellphi-301-nejm-2023/"},{"id":"paper-rudin-sclc-molecular-subtypes-nat-rev-cancer-2019","kind":"paper","name":"Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data","route":"/key-papers/paper-rudin-sclc-molecular-subtypes-nat-rev-cancer-2019/"},{"id":"paper-gay-sclc-subtypes-inflamed-cancer-cell-2021","kind":"paper","name":"Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities","route":"/key-papers/paper-gay-sclc-subtypes-inflamed-cancer-cell-2021/"},{"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/"}],"technology":[{"id":"radioimmunotherapy","kind":"technology","name":"Radio-antibody & radio-ADC","route":"/technologies/radioimmunotherapy/"},{"id":"t-cell-engager","kind":"technology","name":"T-cell engagers (bispecific)","route":"/technologies/t-cell-engager/"}],"person":[{"id":"charles-rudin","kind":"person","name":"Charles M. Rudin","route":"/people/charles-rudin/"}],"bottleneck":[{"id":"b-tme-immunosuppression","kind":"bottleneck","name":"Cold tumours and the immunosuppressive microenvironment","route":"/bottlenecks/b-tme-immunosuppression/"}],"term":[{"id":"cancer-stem-cell-theory","kind":"term","name":"Cancer stem cell theory and phenotypic plasticity","route":"/terms/cancer-stem-cell-theory/"},{"id":"unlocking-phenotypic-plasticity","kind":"term","name":"Hallmark (2022): unlocking phenotypic plasticity","route":"/terms/unlocking-phenotypic-plasticity/"},{"id":"sclc-molecular-subtypes","kind":"term","name":"Small-cell lung cancer transcription-factor subtypes (SCLC-A, SCLC-N, SCLC-P, SCLC-I) and SLFN11","route":"/terms/sclc-molecular-subtypes/"}],"institution":[{"id":"12-de-octubre","kind":"institution","name":"Hospital Universitario 12 de Octubre","route":"/institutions/12-de-octubre/"}]}}