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Updated: Jan 17, 2026
Comparative Lesions Analysis Through a Targeted Sequencing Approach
Published on: November 5, 2019
Clinical and Pathologic Landscapes of Delta-Like Ligand 3 and Seizure-Related Homolog Protein 6 Expression in
Jessica S Ross1, Rohit Thummalapalli2, Kristine Lacuna3,4
1Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
Purpose:
Delta-like ligand 3 (DLL3) and seizure-related homolog protein 6 (SEZ6) are appealing drug targets in neuroendocrine carcinomas (NECs) given their preferential expression on the tumor cell surface compared with normal cells. We aimed to describe the landscape of these proteins across NECs from eight different primary sites.
Patients And Methods:
We used immunohistochemistry to assess 124 NEC tumor samples from any primary site for DLL3 and 53 for SEZ6 and defined positivity as ≥1% staining.
Results:
DLL3 and SEZ6 were commonly expressed in our cohort (97 of 124, 78% and 43 of 53, 81% positivity rates, respectively) and frequently coexpressed when both tested (35 of 53, 66%). NECs of the breast, prostate, and GI system had the highest rates of DLL3 positivity (2 of 2, 100%; 15 of 16, 94%; and 14 of 17, 82%, respectively); all primary sites except lung exhibited 100% positivity rates for SEZ6. DLL3 expression and SEZ6 expression were seen in transformed NECs (12 of 17, 71% and 3 of 4, 75%, respectively) and in brain metastases (5 of 7, 71% and 1 of 2, 50%, respectively). Expression of both proteins tended to remain stable among 10 patients with serial biopsies. DLL3 expression did not affect progression-free survival (PFS) on first-line platinum/etoposide with or without immunotherapy among patients with metastatic lung NEC (median PFS 5.3 v 5.7 months in DLL3+ v DLL3-, P = .9) but was associated with longer overall survival (median 12.5 v 2.6 months, P = .03).
Conclusion:
We describe the landscape of DLL3 and SEZ6 coexpression across NECs, establishing a broad-based cohort of patients who might derive benefit from therapeutics in development targeting these cell surface determinants.
Insights
Delta-like ligand 3 (DLL3) and seizure-related homolog protein 6 (SEZ6) are highly expressed in neuroendocrine carcinomas (NECs). This study establishes a broad cohort for targeted therapeutics, with DLL3 expression linked to improved overall survival in lung NEC.
Area of Science:
- Oncology
- Molecular Biology
- Biomarker Discovery
Background:
- Neuroendocrine carcinomas (NECs) present a therapeutic challenge.
- Delta-like ligand 3 (DLL3) and seizure-related homolog protein 6 (SEZ6) are cell surface proteins with preferential expression on NECs.
- These proteins represent promising targets for novel NEC therapies.
Purpose of the Study:
- To investigate the expression landscape of DLL3 and SEZ6 across various NEC primary sites.
- To determine the coexpression patterns of DLL3 and SEZ6 in NEC.
- To evaluate the potential of these proteins as biomarkers for therapeutic development.
Main Methods:
- Immunohistochemistry was utilized to assess DLL3 and SEZ6 expression in 124 and 53 NEC tumor samples, respectively.
- Positivity was defined as ≥1% tumor cell staining.
- Serial biopsies were analyzed to assess expression stability.
Main Results:
- DLL3 and SEZ6 showed high positivity rates (78% and 81%, respectively) and frequent coexpression (66%) in the NEC cohort.
- Highest DLL3 positivity was observed in breast, prostate, and GI NECs; SEZ6 was highly expressed across most sites.
- DLL3 expression was associated with longer overall survival in metastatic lung NEC patients, but not progression-free survival.
Conclusions:
- DLL3 and SEZ6 are broadly expressed and frequently coexpressed in NECs.
- This study identifies a significant patient cohort potentially benefiting from DLL3- and SEZ6-targeted therapies.
- DLL3 expression may serve as a prognostic marker in lung NEC, warranting further investigation.
