SEZ6: An Emerging Role in Neuroendocrine Carcinomas

SEZ6 is a neuronal membrane protein now implicated in high-grade neuroendocrine carcinomas. These tumors are clinically aggressive and lack durable systemic therapies, heightening the need for precise, druggable targets.

SEZ6 is a type I transmembrane protein whose extracellular SCR and CUB domains mediate protein–protein interactions and local signaling—features consistent with roles in cell adhesion and complement regulation. Although expression is largely neuronal, SEZ6 is aberrantly upregulated in neuroendocrine tumor cells, linking lineage-specific transcriptional programs to a membrane-localized signaling hub. Functionally, SEZ6 can modulate extracellular proteolysis and complement activity, plausibly altering tumor–microenvironment interactions and cell survival; its membrane localization and extracellular domains therefore make it both a mechanistic marker and an accessible therapeutic target.

That tumor-selective expression gives SEZ6 promising biomarker characteristics in high-grade neuroendocrine tumors. Tissue surveys report frequent SEZ6 detection by immunohistochemistry across neuroendocrine carcinomas, with early studies showing high sensitivity and specificity for available antibody clones; RNA datasets also show enrichment in neuroendocrine transcriptional subtypes. In practice, IHC is the leading assay platform, but assay thresholds, inter-clone variability, and potential cross-reactivity with SEZ6 family members remain challenges that require standardization. Prospective, standardized studies are therefore needed to confirm prognostic value and optimal assay parameters.

Preclinical models and early clinical development have centered on antibody-drug conjugates against SEZ6 and demonstrate target-dependent antitumor activity. In xenograft and patient-derived models, SEZ6-targeted ADCs caused tumor regression when tumors met prespecified IHC thresholds, and early-phase clinical cohorts have reported objective responses in pretreated patients. Safety profiles vary by payload: calicheamicin-linked constructs produced hepatotoxicity requiring dose modification, whereas topoisomerase-I payload ADCs have shown encouraging response rates with mainly hematologic toxicity. These data support proof-of-concept efficacy, but payload selection and careful dose-finding are critical before broader implementation.

In small cell lung cancer specifically, SEZ6 is frequently expressed and tracks with neuroendocrine transcriptional states used for patient selection. Large tissue series show SEZ6 positivity across a high proportion of evaluable SCLC samples and enrichment in ASCL1/NE-high subtypes, consistent with SEZ6 as a lineage-associated marker. SCLC therefore offers a concentrated patient population for early SEZ6-directed trials and biomarker-driven enrollment to maximize signal while prospectively capturing expression–response relationships.