From SCLC to epNEC: Understanding the Expanding Role of DLL3 Across Neuroendocrine Carcinomas

Delta-like ligand 3 (DLL3) has become a closely watched biomarker in neuroendocrine oncology. While it first gained prominence in small cell lung cancer (SCLC), evidence of DLL3 expression across neuroendocrine carcinomas (NECs) has broadened interest in its potential role beyond thoracic malignancies.¹ As biomarker-directed therapeutic strategies continue to evolve, understanding where DLL3 fits within neuroendocrine carcinoma clinical practice is becoming increasingly important for both pathologists and oncologists.¹  

DLL3 Biology and Expression Patterns 

DLL3 is an atypical inhibitory ligand in the Notch signaling pathway. Unlike many Notch ligands, DLL3 is minimally expressed in most normal adult tissues but can be highly expressed in high-grade NECs.² In these tumors, DLL3 expression is associated with neuroendocrine lineage programs, including ASCL1-driven biology in SCLC, although the underlying biology and expression patterns may differ across NEC subtypes.² Its restricted expression in normal tissues and enriched expression in aggressive neuroendocrine malignancies has generated interest in DLL3 as a potential therapeutic target.^1,2  

SCLC: The Foundation of DLL3 Awareness 

Clinical interest in the DLL3 protein began in SCLC, in which nearly all tumors express the protein.^3,4 Historically, treatment options for patients with SCLC were limited to platinum-based chemotherapy and radiation, highlighting the need for more selective therapeutic approaches.^1,5 The development of DLL3-directed therapies for SCLC demonstrated that this tumor-associated protein could be successfully targeted, establishing DLL3 as a clinically recognizable predictive biomarker in high-grade neuroendocrine disease.^1,2 This represented a significant advance for a patient population with historically poor outcomes and limited therapeutic options.  

Similarities—and Important Differences—Across NECs 

NECs of extrapulmonary origin (epNECs) occur in <10% of cases and are present throughout the gastrointestinal, genitourinary, gynecologic, pancreatobiliary, and other organ systems and include both small cell and large cell morphologies. These tumors share many histopathologic features with SCLC, including high-grade morphology, elevated proliferative activity, frequent necrosis, and expression of traditional neuroendocrine markers.⁶ Consequently, epNEC and SCLC are often managed using platinum-based treatment paradigms, which often do not have a lasting effect on tumor control or overall survival.⁵  

However, epNEC should not simply be viewed as "SCLC outside the lung." Molecular alterations, biology, and treatment response may differ by site of origin. For example, TP53 and RB1 alterations are common across many NECs, whereas other molecular drivers may be site-specific.⁶ These differences reinforce the need for disease-specific evidence rather than direct extrapolation from SCLC. 

DLL3: A Predictive—Not Diagnostic—Biomarker in NEC  

What is the role of DLL3 in high-grade NEC? One of the most important distinctions for clinicians is that DLL3 is not a diagnostic marker. Diagnosis and classification of neuroendocrine neoplasms continue to rely on morphology, mitotic activity, Ki-67 proliferative index, and established neuroendocrine markers such as synaptophysin, chromogranin, and INSM1.^5,7 Instead, DLL3 is an emerging predictive and therapeutic biomarker, but a lack of a standardized immunohistochemical kit for assessment of DLL3 expression remains a significant barrier.¹ Emerging evidence from ongoing studies of DLL3 overexpression in neuroendocrine neoplasms may translate into its becoming a potential target for new diagnostic techniques and subsequent follow-up.¹ Therefore, the primary clinical role of DLL3 testing is to identify patients who may be candidates for DLL3-directed therapeutic strategies rather than to establish the diagnosis of NEC itself.²  

Why epNEC Is Becoming an Important Area of Investigation 

Interest in DLL3 has expanded beyond SCLC because there remains a substantial unmet need among the epNEC patient population. Patients with advanced epNEC have no validated predictive biomarkers and limited treatment options.¹ Several DLL3-directed therapeutic platforms are now under clinical investigation in epNEC, including bispecific T-cell engagers, chimeric antigen receptor T (CAR-T) cell therapy, antibody-drug conjugates, and other immunotherapeutic approaches, creating growing interest in standardized biomarker assessment for this rare and aggressive disease.¹  

While these therapies remain investigational in epNEC, the evolving clinical landscape underscores an important educational takeaway: DLL3 is no longer a biomarker associated only with SCLC. As evidence continues to emerge, clinicians caring for patients with high-grade NECs should become familiar with DLL3 biology, appropriate biomarker interpretation, and its expanding role in biomarker-directed research across the broader NEC spectrum. 

1. Peddio A, Pietroluongo E, Lamia MR, et al. DLL3 as a potential diagnostic and therapeutic target in neuroendocrine neoplasms: a narrative review. Crit Rev Oncol Hematol. 2024;204:104524. doi:10.1016/j.critrevonc.2024.104524.  

2. Serrano AG, Rocha P, Freitas Lima C, et al. Delta-like ligand 3 (DLL3) landscape in pulmonary and extra-pulmonary neuroendocrine neoplasms. NPJ Precis Oncol. 2024;8:268. doi:10.1038/s41698-024-00739-y. 

3. Ding J, Yeong C. Advances in DLL3-targeted therapies for small cell lung cancer: challenges, opportunities, and future directions. Front Oncol. 2024;14:1504139. doi:10.3389/fonc.2024.1504139.  

4. Ji K, Guo L, Zuo D, et al. Harnessing delta-like ligand 3: bridging biomarker discovery to next-generation immunotherapies in refractory small cell lung cancer. Front Immunol. 2025;16:1592291. doi:10.3389/fimmu.2025.1592291.  

5. Frizziero M, Kilgour E, Simpson KL, et al. Expanding therapeutic opportunities for extra-pulmonary neuroendocrine carcinoma. Clin Cancer Res. 2022;28(10):1999-2019. doi:10.1158/1078-0432.CCR-21-3058.  

6. Stumpo S, Formelli MG, Persano I, et al. Extrapulmonary neuroendocrine carcinomas: current management and future perspectives. J Clin Med. 2023;12(24):7715. doi:10.3390/jcm12247715. 

7. La Rosa S. Challenges in high-grade neuroendocrine neoplasms and mixed neuroendocrine/non-neuroendocrine neoplasms. Endocr Pathol. 2021;32(2):245-257. doi:10.1007/s12022-021-09676-z.