SEZ6 expression and lineage plasticity in small cell lung cancer and transformed non-small cell lung cancer

Small cell lung cancer (SCLC) and extrapulmonary neuroendocrine (NE) tumors are aggressive malignancies with limited treatment options. Seizure-related homolog 6 (SEZ6) is a potential therapeutic target, but its expression in these tumors remains poorly understood. Lineage plasticity contributes to resistance in non-small cell lung cancer (NSCLC), where some cases can undergo SCLC-transformation after targeted therapy. We aimed to characterize SEZ6 expression across NE tumors and presumed NSCLC-to-SCLC transformations.

DNA and RNA sequencing were performed for SCLC, NSCLC, and NE samples. Samples were stratified by SEZ6 RNA expression quartiles and classified into subtypes based on ASCL1, NEUROD1, and POU2F3 expression. Significance was tested using the Mann-Whitney U test. Real-world overall survival was obtained from insurance claims data, with p-values calculated using the log-rank test. Paired samples for NSCLC-to-SCLC transformation were identified by sequential biopsies classified as NSCLC followed by SCLC.

RNA sequencing was performed on 1318 SCLC and 2218 NE samples. Median SEZ6expression was higher in SCLC (39.7 transcripts per million (TPM)) than in NE tumors (20.8 TPM, p<0.0001) and NSCLC (1.34 TPM, p<0.001). Among NE tumors, median SEZ6 expression was highest in prostate (52.0 TPM, p=0.0016 vs SCLC) and lowest in adrenal gland tumors (1.2 TPM, p<0.0001 vs SCLC). In SCLC,SEZ6expression was positively correlated with ASCL1(p=0.44, p<0.0001) andNEUROD1(p=0.16, p<0.0001) expression but notPOU2F3(p=-0.04, p=0.1253). Median survival was longest in SEZ6-Q2 for both SCLC and NE (13.0 mos. and 33.7 mos., respectively). NSCLC-to-SCLC transformation samples showed numerically higher SEZ6 expression post-transformation (median: 86.2 vs 2.4 TPM).

SEZ6expression is higher in SCLC than in NE tumors, with notable heterogeneity by subtype, warranting consideration of expanded use of SEZ6-directed therapy. Translational Relevance Statement: This study establishes SEZ6 as a promising therapeutic target in small cell lung cancer (SCLC) and transformed non-small cell lung cancer (NSCLC), demonstrating its significantly elevated expression compared to neuroendocrine (NE) tumors and NSCLC. The positive correlation of SEZ6 expression with NE lineage markers, particularly in ASCL1 and NEUROD1 subtypes, highlights its role as a lineage-specific marker, guiding the development of SEZ6-targeted antibody-drug conjugates (ADCs). Additionally, the increased SEZ6 expression following NSCLC-to-SCLC transformation suggests that SEZ6-targeted therapies could address resistance mechanisms in transformed tumors. Importantly, the association between high SEZ6 expression and shorter survival indicates that integrating SEZ6 status into diagnostic workflows could help stratify patients by risk and guide therapeutic decision-making. The findings from this study will inform future clinical trials, aiming to implement SEZ6-targeted treatments as part of precision oncology strategies for aggressive NE malignancies.