Affinage

DLL3

Delta-like protein 3 · UniProt Q9NYJ7

Length
618 aa
Mass
64.6 kDa
Annotated
2026-04-28
100 papers in source corpus 18 papers cited in narrative 18 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DLL3 is a divergent Delta/Serrate/LAG-2 (DSL) family Notch ligand that functions as a dedicated cis-inhibitor of Notch signaling rather than a canonical trans-activating ligand, playing essential roles in somitogenesis, neurogenesis, and neuroendocrine tumor biology. Unlike DLL1, DLL3 does not bind Notch receptors in trans or trigger transendocytosis of the Notch extracellular domain — a deficiency traced to its lysine-free intracellular domain, which cannot be ubiquitinated for the force-generating endocytic step required for Notch activation (PMID:16144902, PMID:18676613). In the presomitic mesoderm, DLL3 cooperates with Lunatic fringe (LFNG) to modulate oscillatory Notch activation in the segmentation clock; its O-fucosylation by POFUT1 is dispensable for cis-inhibition in vitro but essential for somitogenesis in vivo, and loss-of-function mutations in DLL3 cause autosomal recessive spondylocostal dysostosis in humans (PMID:10742114, PMID:25856312, PMID:35429490). DLL3 transcription is driven by Ascl1/Neurog2 in neural progenitors and is positioned downstream of N-Myc (regulated by Huwe1) to promote neurogenesis; in SCLC, DLL3 is aberrantly surface-expressed and promotes tumor cell migration and invasion through upregulation of SNAI1 (PMID:19389376, PMID:19686682, PMID:30874360).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1997 Medium

    Initial gain-of-function studies in Xenopus established DLL3 as a functional Delta homologue capable of activating Notch and inhibiting neurogenesis when overexpressed, framing it as a conventional Notch ligand — a view later overturned.

    Evidence Ectopic expression of mouse Dll3 in Xenopus embryos

    PMID:9272948

    Open questions at the time
    • Overexpression artifacts may not reflect endogenous function
    • No loss-of-function data
    • No binding mode characterized
  2. 1998 High

    Positional cloning of the pudgy mouse mutation revealed that Dll3 loss disrupts somite boundary formation and rostrocaudal patterning, establishing its non-redundant requirement in the Notch-dependent segmentation pathway.

    Evidence Positional cloning, complementation testing, and molecular marker analysis in pudgy mutant mice

    PMID:9662403

    Open questions at the time
    • Mechanism of DLL3 action in somitogenesis unclear
    • Relationship to other Delta ligands not resolved
  3. 2000 High

    Human genetic studies linked loss-of-function DLL3 mutations to autosomal recessive spondylocostal dysostosis, confirming the conserved requirement for DLL3 in vertebral segmentation and pinpointing the EGF-like repeat domain as functionally critical.

    Evidence Sequencing of DLL3 in spondylocostal dysostosis families identifying truncating and missense mutations

    PMID:10742114

    Open questions at the time
    • Biochemical consequence of individual EGF-repeat mutations not tested
    • No structure-function analysis
  4. 2002 High

    Targeted Dll3 null alleles demonstrated that DLL3 is required for proper oscillatory expression of segmentation clock genes (Lfng, Hes1, Hes5, Hey1), placing DLL3 upstream of the oscillatory machinery rather than merely responding to it.

    Evidence Gene targeting (null allele) with in situ hybridization of cycling genes in mouse embryos

    PMID:11923214

    Open questions at the time
    • Whether DLL3 directly modulates the clock or acts indirectly through Notch signaling levels was unclear
  5. 2003 High

    Genetic epistasis between Dll1, Dll3, and Mesp2 revealed that these two Delta ligands have non-redundant, potentially counteracting roles in somite patterning, with Mesp2 acting downstream of both.

    Evidence Compound mutant mouse analysis with gene expression profiling

    PMID:12900443

    Open questions at the time
    • Molecular basis for counteracting functions not identified
    • Direct protein interactions not tested
  6. 2005 High

    The pivotal mechanistic question — whether DLL3 is a Notch activator or inhibitor — was resolved: DLL3 does not bind Notch in trans or activate signaling but instead cell-autonomously inhibits Notch in cis, explaining the paradoxical loss-of-function phenotype and redefining DLL3 as a dedicated cis-inhibitor.

    Evidence Multiple Notch activation, trans-binding, co-culture signaling, Xenopus neurogenesis, and neural progenitor differentiation assays

    PMID:16144902

    Open questions at the time
    • Structural basis for inability to signal in trans unknown
    • Mechanism of cis-inhibition at the molecular level unresolved
  7. 2008 High

    The inability of DLL3 to activate Notch was traced to its lysine-free intracellular domain, which cannot mediate ubiquitin-dependent transendocytosis of the Notch extracellular domain — the mechanical step required for signal activation — even when the ectodomain is replaced with that of DLL1.

    Evidence Chimeric DLL1/DLL3 ligand construction with endocytosis, recycling, Notch1 binding, and transendocytosis assays in cell culture

    PMID:18676613

    Open questions at the time
    • Whether additional ectodomain features contribute to the lack of trans-signaling not fully excluded
    • In vivo validation of chimera phenotype not performed
  8. 2009 High

    Three independent studies placed DLL3 within defined transcriptional and signaling networks: Ascl1/Neurog2 directly bind the Dll3 promoter to drive expression in neural tube; the Huwe1–N-Myc axis regulates DLL3 upstream to control neural stem cell expansion; and DLL3 is specifically required for Nrarp oscillation independently of Lfng.

    Evidence Transgenic reporters with E-box mutagenesis plus in vitro binding (Dll3 promoter); conditional Huwe1 KO with cortical neurogenesis phenotyping; Dll3/Lfng null expression analysis

    PMID:19268448 PMID:19389376 PMID:19686682

    Open questions at the time
    • Whether Ascl1-driven DLL3 expression is direct in presomitic mesoderm not tested
    • Downstream effectors linking DLL3 cis-inhibition to Nrarp oscillation unknown
  9. 2015 High

    O-fucosylation of DLL3 EGF repeats by POFUT1 was shown to be essential for in vivo somitogenesis function but dispensable for cis-inhibition in vitro, revealing a separable requirement for glycosylation during segmentation clock operation; DLL3 and LFNG physically interact in the trans-Golgi.

    Evidence Site-directed mutagenesis of O-fucosylation sites, transgenic rescue in Dll3 null embryos, co-immunoprecipitation, in vitro Notch inhibition assays

    PMID:25856312

    Open questions at the time
    • Molecular basis for why O-fucosylation is required in vivo but not in vitro unclear
    • Structural details of DLL3-LFNG interaction not resolved
  10. 2019 Medium

    In SCLC, DLL3 was shown to have a tumor-promoting role: it drives migration and invasion through SNAI1 upregulation, and DLL3 mRNA is stabilized by LIN28B within a miR-518d-5p regulatory axis.

    Evidence siRNA/overexpression in SCLC lines with transwell assays and xenografts; RIP assay for LIN28B-DLL3 mRNA binding

    PMID:30874360 PMID:31079917

    Open questions at the time
    • Mechanism linking DLL3 to SNAI1 transcription not defined
    • Whether DLL3's tumor role depends on cis-inhibition of Notch or an independent pathway is unresolved
  11. 2022 High

    Compound Dll3/Lfng mutant analysis established that DLL3 and LFNG cooperate in the segmentation clock with DLL3 loss epistatic to LFNG loss, and that DLL3 in cells co-expressing DLL1 and NOTCH1 potentiates signal-sending activity in a glycosylation-modulated manner, providing an integrated model of oscillatory Notch regulation.

    Evidence Genetic epistasis (compound mutants), biochemical demonstration of LFNG modification of DLL3 EGF repeats, cell-based Notch signaling assays

    PMID:35429490

    Open questions at the time
    • How cis-inhibition and signal-sending potentiation are balanced quantitatively during oscillation remains unresolved
    • Direct visualization of DLL3 dynamics in the clock is lacking

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis for DLL3's exclusive cis-inhibitory mode, the mechanism by which DLL3 upregulates SNAI1 in tumor cells, and whether DLL3's role in SCLC is Notch-dependent or involves Notch-independent signaling.
  • No crystal or cryo-EM structure of DLL3 alone or in complex with Notch
  • Molecular pathway connecting DLL3 to SNAI1 in SCLC undefined
  • Whether DLL3 ubiquitination by MIB2 (observed in oocytes) is generalizable to other tissues is untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 3 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-1266738 Developmental Biology 6 R-HSA-162582 Signal Transduction 5 R-HSA-1643685 Disease 2
Partners
ASCL1DLL1LFNGLIN28BMESP2NEUROG2NOTCH1SNAI1

Evidence

Reading pass · 18 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 Mouse Dll3, a divergent Delta homologue, can activate the Notch receptor and inhibit primary neurogenesis when ectopically expressed in Xenopus, demonstrating it is a functional Delta homologue capable of activating Notch signaling. Ectopic expression in Xenopus embryos (gain-of-function assay) Development Medium 9272948
1998 Loss-of-function mutation in Dll3 (pudgy mouse) disrupts proper formation of morphological borders in early somite formation and rostral-caudal compartment boundaries within somites, establishing Dll3 as required for initiation of patterning of vertebrate paraxial mesoderm via a Notch-signalling pathway. Positional cloning, complementation testing, histological and molecular marker analyses in pudgy (pu) mouse mutants Nature genetics High 9662403
2000 Mutations in human DLL3, including truncating mutations in conserved extracellular domains and a missense mutation in the fifth EGF repeat, cause autosomal recessive spondylocostal dysostosis, establishing that the EGF-like repeat domain is functionally critical. Mutational analysis (sequencing) of DLL3 in spondylocostal dysostosis families; functional inference from domain conservation Nature genetics High 10742114
2002 Loss-of-function mutation in mouse Dll3 (targeted null allele Dll3neo) causes disruption of the segmentation clock in the presomitic mesoderm, evidenced by perturbed oscillatory expression of Lfng, Hes1, Hes5, and Hey1, resulting in delayed and irregular somite formation and loss of anteroposterior somite polarity. Gene targeting (null allele), expression analysis of cycling genes by in situ hybridization in mutant embryos Development High 11923214
2003 Dll1 and Dll3 operate in feedback loops with Mesp2 for rostrocaudal patterning of somites; genetic epistasis analysis shows Dll1 and Dll3 have non-redundant and potentially counteracting functions in the presomitic mesoderm, with Mesp2 acting downstream of both Notch ligands. Genetic epistasis analysis using Dll1, Dll3, Mesp2, and Psen1 mutant mice; gene expression analysis in compound mutants Development High 12900443
2004 The Dll3 pudgy mutation differentially disrupts cycling (Lfng, Hes7) versus stage-specific (Hey3, Mesp2) genes in paraxial mesoderm, suggesting Dll3 participates in more than one oscillatory mechanism during somitogenesis. Expression analysis of cycling and stage-specific genes in Dll3 pudgy mutant embryos by in situ hybridization Genesis Medium 15170697
2005 DLL3 does not activate Notch signaling (unlike other DSL ligands); it does not bind Notch receptors in trans and Notch1 does not bind DLL3-expressing cells, but DLL3 cell-autonomously suppresses Notch signaling (cis-inhibition), promoting neurogenesis and inhibiting glial differentiation. Together with lunatic fringe, DLL3 modulates Notch signaling levels induced by other DSL ligands. Multiple Notch activation assays, cell-binding assays (trans-binding), co-culture signaling assays, Xenopus neurogenesis assay, mouse neural progenitor differentiation assay Journal of Cell Biology High 16144902
2007 Dll3-Notch1 double heterozygous mice exhibit localized segmental vertebral anomalies and craniofacial defects not seen in single heterozygotes, demonstrating a genetic interaction between Dll3 ligand and Notch1 receptor in axial segmentation and craniofacial development. Compound mutant mouse analysis (double heterozygosity), skeletal phenotyping, microarray gene expression Developmental Dynamics Medium 17849441
2008 The intracellular domain of Dll3 (which contains no lysine) directs endocytosis and recycling via an ubiquitination-independent signal; a Dll1-Dll3 chimera (Dll1 ectodomain + Dll3 transmembrane/intracellular domain) is endocytosed, recycled, and binds Notch1 but cannot induce transendocytosis of the Notch1 extracellular region and therefore cannot activate Notch signaling, indicating that transendocytosis—not merely receptor binding—is required for Notch activation and that the Dll3 intracellular domain specifically lacks this capacity. Chimeric ligand construction, endocytosis/recycling assays, Notch1 binding assays, transendocytosis assays in cell culture PNAS High 18676613
2009 The ubiquitin ligase Huwe1 restrains neural stem cell proliferation and enables neurogenesis by suppressing the N-Myc–DLL3 cascade; loss of Huwe1 in the mouse cortex leads to uncontrolled expansion of neural stem cells associated with upregulation of DLL3, placing DLL3 downstream of N-Myc and upstream of Notch in neural stem cell regulation. Conditional Huwe1 knockout in mouse brain, loss- and gain-of-function experiments, cortical layering and neurogenesis phenotyping Developmental Cell High 19686682
2009 Dll3 is required for normal cyclical expression of Nrarp (a Notch/Wnt regulator) in the presomitic mesoderm during somitogenesis; in Dll3 null embryos Nrarp shows static (non-cycling) expression, while Lfng null embryos eventually resume Nrarp cycling, indicating that Dll3 is specifically required for Nrarp oscillation independently of Lfng. Microdissection of somitic/presomitic mesoderm, gene expression analysis by in situ hybridization in Dll3 null, Lfng null, and Wnt3a null embryos Developmental Biology Medium 19268448
2009 The bHLH transcription factors Ascl1 (Mash1) and Neurog2 form novel DNA-binding complexes (including Ascl1/Ascl1 homodimers and Ascl1/Neurog2 heterodimers) that bind E-boxes in the conserved proximal Dll3 promoter to regulate Dll3 expression in the dorsal neural tube; individual E-boxes function as distinct enhancers or repressors. Transgenic mouse reporter assays, E-box mutagenesis, in vitro DNA-binding assays, loss-of-function analysis of Ascl1 and Neurog2 Developmental Biology High 19389376
2015 O-fucosylation of DLL3 EGF-like repeats 2 and 5 (at POFUT1 consensus sites) is essential for DLL3 function during somitogenesis in vivo; O-fucosylation-deficient DLL3 can still interact with LFNG, Notch1, and DLL1 and retains cis-inhibitory activity in vitro, but cannot rescue the Dll3 null somitogenesis defect, and DLL3 and LFNG interact physically within the trans-Golgi. Site-directed mutagenesis of O-fucosylation sites, transgenic rescue experiments in Dll3 null embryos, co-immunoprecipitation of DLL3 and LFNG, in vitro Notch inhibition assays PLoS ONE High 25856312
2019 DLL3 promotes migration and invasion of SCLC cells by positively regulating SNAI1 (Snail) expression; DLL3 knockdown reduced migration/invasion and SNAI1 levels, while DLL3 overexpression increased them, and SNAI1 knockdown attenuated DLL3-driven migration/invasion. DLL3 overexpression also promoted subcutaneous tumor growth in mice. Loss-of-function (siRNA knockdown) and gain-of-function (overexpression) in SCLC cell lines, transwell migration/invasion assay, SNAI1 expression analysis, mouse xenograft model Cancer Science Medium 30874360
2019 DLL3 mRNA is stabilized by the RNA-binding protein LIN28B, and both LIN28B and DLL3 are downstream targets of miR-518d-5p; this miR-518d-5p/LIN28B/DLL3 axis regulates SCLC cell proliferation and migration. RIP assay (LIN28B-DLL3 mRNA interaction), miRNA overexpression/inhibition, rescue assays in SCLC cell lines Biochemical and Biophysical Research Communications Medium 31079917
2021 Gm364 (a multi-pass transmembrane protein) directly binds and anchors the ubiquitin ligase MIB2 on the membrane, which then ubiquitinates and activates DLL3; activated DLL3 binds and activates Notch2, whose intracellular domain (NICD2) directly activates AKT to regulate oocyte meiosis and quality. Global Gm364 knockout mouse, co-immunoprecipitation, ubiquitination assays, oocyte phenotyping (ROS, mitochondrial membrane potential, aneuploidy) Cell Death and Differentiation Medium 34635817
2022 DLL3 and LFNG cooperate in the segmentation clock: loss of Dll3 is epistatic to loss of Lfng in the presomitic mesoderm, causing strong reductions in Notch activity in the caudal PSM; LFNG directly modifies EGF repeats on DLL1 and DLL3; DLL3 expression in cells co-expressing DLL1 and NOTCH1 potentiates signal-sending activity in a manner modulated by LFNG, suggesting coordinated regulation of oscillatory Notch activation via glycosylation and cis-inhibition. Genetic epistasis analysis (Dll3/Lfng compound mutants), biochemical demonstration of LFNG modification of DLL1 and DLL3 EGF repeats, cell-based Notch signaling assays Developmental Biology High 35429490
2022 High levels of DLL3 in SCLC cells promote expansion of a cell population with lower expression of both neuroendocrine and non-neuroendocrine markers, acting as a biomarker of neuroendocrine state and regulator of cell-cell Notch interactions; this was demonstrated using a single-chain variable fragment (scFv) to track DLL3 in vivo and a mouse SCLC model with inducible DLL3 expression. Mathematical modeling, in vivo DLL3 tracking with scFv, inducible DLL3 mouse SCLC model, cell population analysis iScience Medium 36483011

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo. Science translational medicine 473 26311731
2016 Rovalpituzumab tesirine, a DLL3-targeted antibody-drug conjugate, in recurrent small-cell lung cancer: a first-in-human, first-in-class, open-label, phase 1 study. The Lancet. Oncology 452 27932068
1997 Mouse Dll3: a novel divergent Delta gene which may complement the function of other Delta homologues during early pattern formation in the mouse embryo. Development (Cambridge, England) 320 9272948
2000 Mutations in the human delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis. Nature genetics 306 10742114
2019 Efficacy and Safety of Rovalpituzumab Tesirine in Third-Line and Beyond Patients with DLL3-Expressing, Relapsed/Refractory Small-Cell Lung Cancer: Results From the Phase II TRINITY Study. Clinical cancer research : an official journal of the American Association for Cancer Research 258 31506387
2023 Tarlatamab, a First-in-Class DLL3-Targeted Bispecific T-Cell Engager, in Recurrent Small-Cell Lung Cancer: An Open-Label, Phase I Study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 237 36689692
1998 The mouse pudgy mutation disrupts Delta homologue Dll3 and initiation of early somite boundaries. Nature genetics 237 9662403
2005 The divergent DSL ligand Dll3 does not activate Notch signaling but cell autonomously attenuates signaling induced by other DSL ligands. The Journal of cell biology 233 16144902
2021 Efficacy and Safety of Rovalpituzumab Tesirine Compared With Topotecan as Second-Line Therapy in DLL3-High SCLC: Results From the Phase 3 TAHOE Study. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 223 33607312
2020 AMG 757, a Half-Life Extended, DLL3-Targeted Bispecific T-Cell Engager, Shows High Potency and Sensitivity in Preclinical Models of Small-Cell Lung Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 190 33203642
2019 DLL3: an emerging target in small cell lung cancer. Journal of hematology & oncology 189 31215500
2002 Axial skeletal defects caused by mutation in the spondylocostal dysplasia/pudgy gene Dll3 are associated with disruption of the segmentation clock within the presomitic mesoderm. Development (Cambridge, England) 177 11923214
2023 IL-18-secreting CAR T cells targeting DLL3 are highly effective in small cell lung cancer models. The Journal of clinical investigation 144 36951942
2009 The N-Myc-DLL3 cascade is suppressed by the ubiquitin ligase Huwe1 to inhibit proliferation and promote neurogenesis in the developing brain. Developmental cell 139 19686682
2023 Emerging therapies targeting the delta-like ligand 3 (DLL3) in small cell lung cancer. Journal of hematology & oncology 130 37355629
2003 Novel mutations in DLL3, a somitogenesis gene encoding a ligand for the Notch signalling pathway, cause a consistent pattern of abnormal vertebral segmentation in spondylocostal dysostosis. Journal of medical genetics 110 12746394
2017 Noninvasive Interrogation of DLL3 Expression in Metastatic Small Cell Lung Cancer. Cancer research 92 28487384
2009 Ascl1 and Neurog2 form novel complexes and regulate Delta-like3 (Dll3) expression in the neural tube. Developmental biology 89 19389376
2020 A Bispecific DLL3/CD3 IgG-Like T-Cell Engaging Antibody Induces Antitumor Responses in Small Cell Lung Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 79 32554516
2019 DLL3 regulates the migration and invasion of small cell lung cancer by modulating Snail. Cancer science 79 30874360
2003 Feedback loops comprising Dll1, Dll3 and Mesp2, and differential involvement of Psen1 are essential for rostrocaudal patterning of somites. Development (Cambridge, England) 77 12900443
2008 The intracellular region of Notch ligands Dll1 and Dll3 regulates their trafficking and signaling activity. Proceedings of the National Academy of Sciences of the United States of America 71 18676613
2022 CAR NK-92 cells targeting DLL3 kill effectively small cell lung cancer cells in vitro and in vivo. Journal of leukocyte biology 68 35088475
2022 DLL3 as an Emerging Target for the Treatment of Neuroendocrine Neoplasms. The oncologist 66 35983951
2020 Combined DLL3-targeted bispecific antibody with PD-1 inhibition is efficient to suppress small cell lung cancer growth. Journal for immunotherapy of cancer 64 32554616
2020 International real-world study of DLL3 expression in patients with small cell lung cancer. Lung cancer (Amsterdam, Netherlands) 62 32745892
2018 Cell Surface Notch Ligand DLL3 is a Therapeutic Target in Isocitrate Dehydrogenase-mutant Glioma. Clinical cancer research : an official journal of the American Association for Cancer Research 60 30397180
2023 Targeting the Notch signaling pathway and the Notch ligand, DLL3, in small cell lung cancer. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 54 36645960
2022 Phase I trial of the DLL3/CD3 bispecific T-cell engager BI 764532 in DLL3-positive small-cell lung cancer and neuroendocrine carcinomas. Future oncology (London, England) 54 35815644
2019 DLL3 expression in large cell neuroendocrine carcinoma (LCNEC) and association with molecular subtypes and neuroendocrine profile. Lung cancer (Amsterdam, Netherlands) 53 31678831
2023 Immunotherapeutic Targeting and PET Imaging of DLL3 in Small-Cell Neuroendocrine Prostate Cancer. Cancer research 52 36351060
2020 Near infrared photoimmunotherapy targeting DLL3 for small cell lung cancer. EBioMedicine 50 31981983
2019 Analysis of DLL3 and ASCL1 in Surgically Resected Small Cell Lung Cancer (HOT1702). The oncologist 48 31068386
2018 LncRNA LINC00311 Promotes the Proliferation and Differentiation of Osteoclasts in Osteoporotic Rats Through the Notch Signaling Pathway by Targeting DLL3. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 46 29975944
2015 O-fucosylation of DLL3 is required for its function during somitogenesis. PloS one 46 25856312
2023 Allogeneic CAR T Cells Targeting DLL3 Are Efficacious and Safe in Preclinical Models of Small Cell Lung Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 45 36692420
2021 Diagnostic and Predictive Role of DLL3 Expression in Gastroenteropancreatic Neuroendocrine Neoplasms. Endocrine pathology 43 33409812
2009 Cyclical expression of the Notch/Wnt regulator Nrarp requires modulation by Dll3 in somitogenesis. Developmental biology 40 19268448
2024 DLL3-guided therapies in small-cell lung cancer: from antibody-drug conjugate to precision immunotherapy and radioimmunotherapy. Molecular cancer 39 38730427
2022 DLL3 regulates Notch signaling in small cell lung cancer. iScience 39 36483011
2004 Dll3 pudgy mutation differentially disrupts dynamic expression of somite genes. Genesis (New York, N.Y. : 2000) 39 15170697
2024 Imaging with [89Zr]Zr-DFO-SC16.56 anti-DLL3 antibody in patients with high-grade neuroendocrine tumours of the lung and prostate: a phase 1/2, first-in-human trial. The Lancet. Oncology 37 38950555
2007 Dll3 and Notch1 genetic interactions model axial segmental and craniofacial malformations of human birth defects. Developmental dynamics : an official publication of the American Association of Anatomists 33 17849441
2019 DLL3 is regulated by LIN28B and miR-518d-5p and regulates cell proliferation, migration and chemotherapy response in advanced small cell lung cancer. Biochemical and biophysical research communications 32 31079917
2019 Characterization of DLL3-positive circulating tumor cells (CTCs) in patients with small cell lung cancer (SCLC) and evaluation of their clinical relevance during front-line treatment. Lung cancer (Amsterdam, Netherlands) 31 31447000
2023 Clinical Pharmacology Profile of AMG 119, the First Chimeric Antigen Receptor T (CAR-T) Cell Therapy Targeting Delta-Like Ligand 3 (DLL3), in Patients with Relapsed/Refractory Small Cell Lung Cancer (SCLC). Journal of clinical pharmacology 30 37694295
2023 Saikosaponin a activates tet1/dll3/notch1 signalling and promotes hippocampal neurogenesis to improve depression-like behavior in mice. Journal of ethnopharmacology 30 37844745
2018 Rovalpituzumab Tesirine: A Novel DLL3-Targeting Antibody-Drug Conjugate. Drugs in R&D 29 30232719
2024 Assessment of TROP2, CEACAM5 and DLL3 in metastatic prostate cancer: Expression landscape and molecular correlates. NPJ precision oncology 28 38760413
2006 DLL3 as a candidate gene for vertebral malformations. American journal of medical genetics. Part A 27 17041936
2003 A cluster of autosomal recessive spondylocostal dysostosis caused by three newly identified DLL3 mutations segregating in a small village. Clinical genetics 27 12791036
2019 NOTCH2/NOTCH3/DLL3/MAML1/ADAM17 signaling network is associated with ovarian cancer. Oncology letters 25 31186700
2017 EGFL7 participates in regulating biological behavior of growth hormone-secreting pituitary adenomas via Notch2/DLL3 signaling pathway. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 25 28705113
2019 Prevalence of DLL3, CTLA-4 and MSTN Expression in Patients with Small Cell Lung Cancer. OncoTargets and therapy 24 31819500
2020 DLL3 expression is a predictive marker of sensitivity to adjuvant chemotherapy for pulmonary LCNEC. Thoracic cancer 23 32691982
2024 HPN328, a Trispecific T Cell-Activating Protein Construct Targeting DLL3-Expressing Solid Tumors. Molecular cancer therapeutics 22 38670552
2019 Delta-like Protein 3 Prevalence in Small Cell Lung Cancer and DLL3 (SP347) Assay Characteristics. Archives of pathology & laboratory medicine 22 30958693
2019 Comparison of four DLL3 antibodies performance in high grade neuroendocrine lung tumor samples and cell cultures. Diagnostic pathology 22 31109352
2025 Engineered circular RNA-based DLL3-targeted CAR-T therapy for small cell lung cancer. Experimental hematology & oncology 21 40075480
2024 Engineering CD3/CD137 Dual Specificity into a DLL3-Targeted T-Cell Engager Enhances T-Cell Infiltration and Efficacy against Small-Cell Lung Cancer. Cancer immunology research 20 38558120
2024 Small cell transformation in EGFR-mutated non-small cell lung cancer: DLL3 expression and efficacy of immune checkpoint inhibitors or tyrosine kinase inhibitors combined with chemotherapy. European journal of cancer (Oxford, England : 1990) 20 39423775
2024 Delta-like ligand 3 (DLL3) landscape in pulmonary and extra-pulmonary neuroendocrine neoplasms. NPJ precision oncology 19 39558076
2016 Toppling high-grade pulmonary neuroendocrine tumors with a DLL3-targeted trojan horse. Molecular & cellular oncology 19 27308627
2010 Autosomal dominant spondylocostal dysostosis in three generations of a Macedonian family: Negative mutation analysis of DLL3, MESP2, HES7, and LFNG. American journal of medical genetics. Part A 19 20503311
2024 FZ-AD005, a Novel DLL3-Targeted Antibody-Drug Conjugate with Topoisomerase I Inhibitor, Shows Potent Antitumor Activity in Preclinical Models. Molecular cancer therapeutics 18 38940283
2024 DLL3 as a potential diagnostic and therapeutic target in neuroendocrine neoplasms: A narrative review. Critical reviews in oncology/hematology 18 39326646
2021 ASCL1 and DLL3 expressions and their clinicopathological implications in surgically resected pure small cell lung cancer: A study of 247 cases from the National Cancer Center of China. Thoracic cancer 18 34931456
2020 Rova-T enhances the anti-tumor activity of anti-PD1 in a murine model of small cell lung cancer with endogenous Dll3 expression. Translational oncology 18 33074129
2001 Dynamic expression patterns of the pudgy/spondylocostal dysostosis gene Dll3 in the developing nervous system. Mechanisms of development 18 11118901
2024 DB-1314, a novel DLL3-targeting ADC with DNA topoisomerase I inhibitor, exhibits promising safety profile and therapeutic efficacy in preclinical small cell lung cancer models. Journal of translational medicine 17 39143619
2001 Differential and overlapping expression patterns of X-dll3 and Pax-6 genes suggest distinct roles in olfactory system development of the African clawed frog Xenopus laevis. The Journal of experimental biology 16 11441047
2021 DLL3 (delta-like protein 3) expression correlates with stromal desmoplasia and lymph node metastases in medullary thyroid carcinomas. Endocrine connections 15 33617464
2024 TREM1/DAP12 based novel multiple chain CAR-T cells targeting DLL3 show robust anti-tumour efficacy for small cell lung cancer. Immunology 14 38469682
2024 Advances in DLL3-targeted therapies for small cell lung cancer: challenges, opportunities, and future directions. Frontiers in oncology 14 39703856
2021 Gm364 coordinates MIB2/DLL3/Notch2 to regulate female fertility through AKT activation. Cell death and differentiation 14 34635817
2023 Tumor microenvironment-mediated immune profiles and efficacy of anti-PD-L1 antibody plus chemotherapy stratified by DLL3 expression in small-cell lung cancer. British journal of cancer 13 37731022
2021 Synthesis and Comparative In Vivo Evaluation of Site-Specifically Labeled Radioimmunoconjugates for DLL3-Targeted ImmunoPET. Bioconjugate chemistry 13 33835770
2022 Design of two immunotoxins based rovalpituzumab antibody against DLL3 receptor; a promising potential opportunity. Research in pharmaceutical sciences 12 36034078
2004 New mutant mouse with skeletal deformities caused by mutation in delta like 3 (Dll3) gene. Experimental animals 12 15153675
2025 DLL3 Expression in Neuroendocrine Carcinomas and Neuroendocrine Tumours: Insights From a Multicentric Cohort of 1294 Pulmonary and Extrapulmonary Neuroendocrine Neoplasms. Endocrine pathology 11 40153138
2022 Lfng and Dll3 cooperate to modulate protein interactions in cis and coordinate oscillatory Notch pathway activation in the segmentation clock. Developmental biology 11 35429490
2025 Expression Patterns of DLL3 across Neuroendocrine and Non-neuroendocrine Neoplasms Reveal Broad Opportunities for Therapeutic Targeting. Cancer research communications 10 39874041
2025 Exploring the expression of DLL3 in gastroenteropancreatic neuroendocrine neoplasms and its potential diagnostic value. Scientific reports 9 39865119
2022 Evaluation of the DLL3-targeting antibody-drug conjugate rovalpituzumab tesirine in preclinical models of neuroblastoma. Cancer research communications 9 36381237
2022 Harnessing DLL3 inhibition: From old promises to new therapeutic horizons. Frontiers in medicine 8 36530878
2024 Tet1/DLL3/Notch1 signal pathway affects hippocampal neurogenesis and regulates depression-like behaviour in mice. European journal of pharmacology 6 38346470
2024 Pharmacokinetics of Tarlatamab, a Delta-Like Ligand-3 (DLL3) Targeted Half-Life Extended Bispecific T-Cell Engager (BiTE®) Immunotherapy in Adult Patients with Previously Treated Small-Cell Lung Cancer: Results from DeLLphi-300, a Phase I Multiple-Dose-Escalation Study. Clinical pharmacokinetics 6 39589690
2024 First Report of Response to Tarlatamab in a Patient With DLL3-Positive Pulmonary Carcinoid: Case Report. JTO clinical and research reports 6 39619276
2022 Delta-like ligand 3 (DLL3): an attractive actionable target in tumors with neuroendocrine origin. Expert review of anticancer therapy 6 35477310
2025 Population Pharmacokinetics of Tarlatamab, a Half-Life Extended DLL3-Directed Bispecific T-Cell Engager in Patients with Previously Treated Small Cell Lung Cancer. Clinical pharmacokinetics 5 40261494
2025 Targeting DLL3: Innovative Strategies for Tumor Treatment. Pharmaceutics 5 40284515
2024 Relationship between the expressions of DLL3, ASC1, TTF-1 and Ki-67: First steps of precision medicine at SCLC. Oncotarget 5 39392394
2023 Identification of a Novel Nonsense Variant in the DLL3 Gene Underlying Spondylocostal Dysostosis in a Consanguineous Pakistani Family. Molecular syndromology 5 37323197
2024 First-in-human imaging with [89Zr]Zr-DFO-SC16.56 anti-DLL3 antibody in patients with high-grade neuroendocrine tumors of the lung and prostate. medRxiv : the preprint server for health sciences 4 38260492
2024 Expression patterns and clinical implications of PDL1 and DLL3 biomarkers in small cell lung cancer retrospectively studied: Insights for therapeutic strategies and survival prediction. Heliyon 4 38468968
2025 Engineered exosomes restore miR-508-5p expression in uterine corpus endometrial carcinoma and reduce tumor progression and metastasis by targeting DLL3. Frontiers in oncology 3 40066092
2023 Biological and immunological significance of DLL3 expression in different tumor tissues: a pan-cancer analysis. Aging 3 37179118
2021 Elevated DLL3 in stomach cancer by tumor-associated macrophages enhances cancer-cell proliferation and cytokine secretion of macrophages. Gastroenterology report 3 35382168
2025 Expression of DLL3 and SEZ6 in the Spectrum of Neuroendocrine Neoplasia. Endocrine pathology 2 40699376
2020 Influence of preanalytical variables on performance of delta-like protein 3 (DLL3) predictive immunohistochemistry. Virchows Archiv : an international journal of pathology 2 32488689