DLL3 as an Emerging Target for the Treatment of Neuroendocrine Neoplasms

Oncologist. 2022 Nov 3;27(11):940-951. doi: 10.1093/oncolo/oyac161.


Introduction: Neuroendocrine neoplasms (NEN) are heterogeneous malignancies that can arise at almost any anatomical site and are classified as biologically distinct well-differentiated neuroendocrine tumors (NET) and poorly differentiated neuroendocrine carcinomas (NEC). Current systemic therapies for advanced disease, including targeted therapies, chemotherapy, and immunotherapy, are associated with limited duration of response. New therapeutic targets are needed. One promising target is delta-like ligand 3 (DLL3), an inhibitory ligand of the Notch receptor whose overexpression on the surface of NEN is associated with tumorigenesis.

Methods: This article is a narrative review that highlights the role of DLL3 in NEN progression and prognosis, the potential for therapeutic targeting of DLL3, and ongoing studies of DLL3-targeting therapies. Classification, incidence, pathogenesis, and current management of NEN are reviewed to provide biological context and illustrate the unmet clinical needs.

Discussion: DLL3 is overexpressed in many NENs, implicated in tumor progression, and is typically associated with poor clinical outcomes, particularly in patients with NEC. Targeted therapies using DLL3 as a homing beacon for cytotoxic activity mediated via several different mechanisms (eg, antibody-drug conjugates, T-cell engager molecules, CAR-Ts) have shown promising clinical activity in small-cell lung cancer (SCLC). DLL3 may be a clinically actionable target across NEN.

Conclusions: Current treatment options for NEN do not provide sustained responses. DLL3 is expressed on the cell surface of many NEN types and is associated with poor clinical outcomes. Initial clinical studies targeting DLL3 therapeutically in SCLC have been promising, and additional studies are expanding this approach to the broader group of NEN.

Keywords: DLL3 protein; human; molecular targeted therapy; neuroendocrine carcinoma; neuroendocrine tumors.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Neuroendocrine* / pathology
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Ligands
  • Lung Neoplasms* / drug therapy
  • Membrane Proteins / genetics
  • Neuroendocrine Tumors* / drug therapy
  • Neuroendocrine Tumors* / genetics
  • Neuroendocrine Tumors* / pathology
  • Small Cell Lung Carcinoma* / drug therapy


  • Ligands
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • DLL3 protein, human