Real-World Characterization of SEZ6, a Transmembrane Protein Expressed in Various Solid Tumors

**Background
**Seizure-related homolog 6 (SEZ6) is a transmembrane protein involved in neuronal development that is downregulated in normal adult tissues outside the central nervous system (CNS). It is overexpressed in various solid tumors such as small cell lung cancer (SCLC), neuroendocrine neoplasms (NENs), and CNS tumors, with strong correlations between mRNA and protein expression. In SCLC, limited data suggest that SEZ6 expression is greater in molecular subtypes with neuroendocrine (NE)-high gene signatures (i.e., SCLC-A and SCLC- N) than in non-NE subtypes (i.e., SCLC-P). However, SEZ6 expression in tumor tissues remains poorly understood and existing data are limited by small sample sizes. This study aimed to characterize SEZ6 expression in a large patient population, across multiple tumor types.

Methods
Pan-tumor data from a real-world database (Tempus AI, Inc.) were analyzed for SEZ6 mRNA expression in 37,645 samples, with a focus on lung, brain, and NE tumor types. In SCLC, SEZ6 expression was compared between SCLC-A, -N, -P, and -I samples via hierarchical clustering. Gene expression was reported as log (transcripts per million [TPM]+1).

Results
Across the 37,645 samples analyzed, tumor types with the highest median (log [SEZ6 TPM+1]) expression were astrocytoma (5.8; n = 354), glioma (5.8; n = 502), NENs (5.7; n = 2794), and glioblastoma (5.6, n = 2833). Among NENs, the highest SEZ6 expression was seen in prostate neuroendocrine carcinoma (NEC) (6.6; n = 176), SCLC (6.5; n = 2018), and bladder small cell NEC (6.5; n = 139). Median SEZ6 expression was 3–45-fold higher than other biomarkers of interest in SCLC (B7-H3, 3-fold; DLL3, 3-fold; CD274 [PD-L1], 28-fold; PDCD1 [PD-1], 45-fold). In SCLC samples, median SEZ6 expression was stable across primary (6.4) and metastatic (6.5) tumors and stage II to IV disease (6.6–6.5). Among SCLC molecular subtypes, median SEZ6 expression was lower in non-NE SCLC-P tumors (3.8; n = 85) than in SCLC-I (6.0; n = 175), or in NE-high SCLC-N (6.7; n = 339) and SCLC-A (7.3; n = 224) tumors. SEZ6 expression was 6–7-fold higher in prostate NEC than in non-NE metastatic prostate adenocarcinoma (castration resistant, 6-fold; castration sensitive, 7-fold).

Conclusions
SEZ6 is highly expressed in SCLC and tumors of NE origin, particularly prostate and bladder NEC. In SCLC, SEZ6 expression is higher than other targets of antibody–drug conjugates (ADCs) approved or in development for SCLC, supporting SEZ6 as a promising therapeutic target. SEZ6 expression is highest in SCLC-A and SCLC-N molecular subtypes. High SEZ6 expression is also seen in SCLC-I, a subtype associated with platinum resistance, suggesting SEZ6 may be a potential therapeutic target in certain patients with platinum- refractory SCLC. Taken together, these results suggest cross-indication applicability of targeting SEZ6, highlighting its potential as a multi-tumor ADC target warranting further investigation.