Delta-like ligand 3 (DLL3) landscape in pulmonary and extra-pulmonary neuroendocrine neoplasms

Sep 21, 2026

Uploaded by Quinn

Delta-like ligand 3 (DLL3) targeting therapies show promise in small cell lung cancer (SCLC), but DLL3 expression across neuroendocrine neoplasms (NEN) is heterogeneous and incompletely mapped. This study profiles DLL3 at mRNA and protein levels across SCLC, large cell neuroendocrine carcinoma (LCNEC), and non-small cell lung cancer, and evaluates extra-pulmonary NEN (EP-NEN) using a standardized DLL3 IHC assay. DLL3 is enriched in SCLC and LCNEC, with wide variation in high-grade EP-NEN, supporting future trial design for LCNEC and EP-NEN.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages13

Reading Time33 min

AccessFree to download

Introduction

DLL3 as a therapeutic target

Study approach

Expression profiling across NEN subtypes

Standardized DLL3 IHC assay in EP-NEN

Findings and implications

DLL3 enrichment and heterogeneity

Impact on future clinical trial design

npj | precision oncology Article | Published in partnership with The Hormel Institute, University of Minnesota | | | | --- | --- | --- | | [https://doi.org/10.1038/s41698-024-00739-y](https://doi.org/10.1038/s41698-024-00739-y) | | | | Delta-like ligand 3 (DLL3) landscape in pulmonary and extra-pulmonary neuroendocrine neoplasms
Check for updates | | | | Alejandra G. Serrano1,8, Pedro Rocha1,8, Cibelle Freitas Lima1, Allison Stewart 2, Bingnan Zhang2, Lixia Diao3, Junya Fujimoto1, Robert J. Cardnell2, Wei Lu1, Khaja Khan1, Beate Sable4, Aaron R. Ellison4, Ignacio I. Wistuba1, Kyle F. Concannon2, Daniel M. Halperin5, Czerniak Bogdan6, Kanishka Sircar6, Miao Zhang6, Kasey Cargill2, Qi Wang3, Ana Aparicio7, Alexander Lazar 6, Sharia Hernandez1, Jeannelyn Estrella6, Preetha Ramalingam6, Adel El-Naggar6, Neda Kalhor6, Carl M. Gay2,
Lauren Averett Byers 2,8 & Luisa M. Solis Soto 1,8 | | | | Delta-like Ligand3(DLL3)targeting therapies are promising in small cell lung cancer(SCLC)treatment. However, DLL3 expression in SCLC and other neuroendocrine neoplasms (NEN) is heterogeneous and not well characterized. We describe the landscape of DLL3 atthe mRNA and protein levels across SCLC, large cell neuroendocrine carcinoma (LCNEC), and non-small cell lung cancer. Additionally, we explore its expression in extra-pulmonary NEN (EP-NEN) using a standardized DLL3 IHC assay. DLL3 expression is enriched in SCLC, LCNEC along with combined histology lung cancers. Moreover, we ﬁnd a wide range of DLL3 expression in high-grade EP-NEN. We describe heterogenous DLL3 expression not only in SCLC but also in different NEN types. This comprehensive characterization of DLL3 can help guide future clinical trial design targeting DLL3 in NEN including LCNEC and EP-NEN that are lacking standard of care treatment options. | | | | Delta-like Ligand 3 (DLL3) is an inhibitory Notch ligand frequently upregulated in small cell lung cancer (SCLC) and other neuroendocrine neoplasms (NEN), with minimal expression in normal tissues1,2. DLL3 is a downstream target of transcription factor Achaete-scute homolog 1 (ASCL1), which is a proneural transcription factor that plays an important role in neuroendocrine differentiation3. Speciﬁcally, in SCLC, DLL3 was found to be enriched in the neuroendocrine subtypes of SCLC deﬁned by Gay et al., and characterized by the expression of transcription factors ASCL1 (SCLC-A), and NEUROD1 (SCLC-N), and that accounts for about 80% of SCLC4–6. In recent years, DLL3 has emerged as a promising therapeutic target for the treatment of SCLC and other neuroendocrine tumors. ADLL3-targeting antibody-drug conjugate(ADC)rovalpituzumab tesirine (Rova-T) initially showed promising efﬁcacy signal7,8, but subsequent trials evaluating Rova-T did not demonstrate clinical beneﬁt in patients with relapsed metastatic SCLC9, 10. However, the failure of Rova T is largely | attributed to the pyrrolobenzodiazepine payload toxicities, rather than the expression of DLL3 as a target11. More recently, a ﬁrst-in-human phase 1 study of a DLL3-targeting CAR T (AMG 119) showed safety and promising early efﬁcacy signals inpatients treated atthe lowest dose level, out of 4 evaluable patients, one patient had partial response and one patient had tumor shrinkage10. In addition, tarlatamab (formerly AMG 757), a DLL3-targeting bispeciﬁc T-cell engager recently received FDA accelerated approval in May2024for the treatment ofreleased small cell lung cancer. In the phase 2 DeLLphi-301 study, tarlatamab showed promising clinical efﬁcacy in patients with relapsed SCLC, with an objective response rate of about 40% and 32% at the 10mg and 100 mg dose levels respectively, and the duration of response was at least 6 months in 59% of patients (in the phase 1 study, the median duration of response for tarlatamab was of over a year)11, 12. In such an aggressive disease where the median survival from diagnosis is typically about a year, this result is particularly e

FAQs

Why is DLL3 considered an attractive target in SCLC and other NEN?

DLL3 is an inhibitory Notch ligand upregulated in SCLC and other neuroendocrine neoplasms, with minimal expression in normal tissues. It is also linked to neuroendocrine differentiation pathways.

What does this study evaluate about DLL3?

It characterizes the DLL3 landscape at both mRNA and protein levels across SCLC, LCNEC, and non-small cell lung cancer. It further examines DLL3 expression in extra-pulmonary NEN using a standardized IHC assay.

How does DLL3 expression differ between lung NEN and extra-pulmonary NEN?

DLL3 expression is enriched in SCLC and LCNEC, particularly alongside combined histology lung cancers. In contrast, high-grade extra-pulmonary NEN shows a wide range of DLL3 expression.

Sep 21, 2026

Uploaded by Quinn