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Seizure-Related Homolog Protein 6 (SEZ6) : Biology and Therapeutic Target in Neuroendocrine Carcinomas

Gezelius, Emelie LU ; Rekhtman, Natasha ; Baine, Marina K. ; Rudin, Charles M. ; Drilon, Alexander and Cooper, Alissa J. (2025) In Clinical Cancer Research 31(21). p.4419-4428
Abstract

Seizure-related homolog protein 6 (SEZ6) is a cell surface type 1 transmembrane protein involved in neuronal development, the expression of which in adult tissues is almost exclusively limited to the central nervous system. Aberrant expression of SEZ6 has been associated with neurodevelopmental and psychiatric disorders including epilepsy, schizophrenia, and Alzheimer disease. More recently, SEZ6 overexpression has been detected in small cell lung cancer (SCLC) and other high-grade neuroendocrine malignancies, although our understanding of the function of SEZ6 as a driver of cancer is limited. A lineage-defining transcription factor of SCLC, ASCL1, has been implicated as a regulator of SEZ6 expression. SEZ6 has emerged as a novel target... (More)

Seizure-related homolog protein 6 (SEZ6) is a cell surface type 1 transmembrane protein involved in neuronal development, the expression of which in adult tissues is almost exclusively limited to the central nervous system. Aberrant expression of SEZ6 has been associated with neurodevelopmental and psychiatric disorders including epilepsy, schizophrenia, and Alzheimer disease. More recently, SEZ6 overexpression has been detected in small cell lung cancer (SCLC) and other high-grade neuroendocrine malignancies, although our understanding of the function of SEZ6 as a driver of cancer is limited. A lineage-defining transcription factor of SCLC, ASCL1, has been implicated as a regulator of SEZ6 expression. SEZ6 has emerged as a novel target for antibody–drug conjugate therapy, and early studies have shown promising antitumor activity, demonstrating the potential for SEZ6 to be targeted by drugs with alternate mechanisms of action. In this article, we review the current knowledge of the biology of SEZ6 and its implications in malignancy, summarize the preclinical and clinical findings of SEZ6-targeted antibody–drug conjugates, and discuss future directions to further elucidate the role of SEZ6 in SCLC and other neuroendocrine neoplasms.

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author
; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Clinical Cancer Research
volume
31
issue
21
pages
10 pages
publisher
American Association for Cancer Research Inc.
external identifiers
  • scopus:105020805541
  • pmid:40911432
ISSN
1078-0432
DOI
10.1158/1078-0432.CCR-25-2090
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2025 American Association for Cancer Research.
id
c405287c-07b0-4e73-8ee1-c6a441acca39
date added to LUP
2025-12-11 14:38:10
date last changed
2025-12-12 03:00:14
@article{c405287c-07b0-4e73-8ee1-c6a441acca39,
  abstract     = {{<p>Seizure-related homolog protein 6 (SEZ6) is a cell surface type 1 transmembrane protein involved in neuronal development, the expression of which in adult tissues is almost exclusively limited to the central nervous system. Aberrant expression of SEZ6 has been associated with neurodevelopmental and psychiatric disorders including epilepsy, schizophrenia, and Alzheimer disease. More recently, SEZ6 overexpression has been detected in small cell lung cancer (SCLC) and other high-grade neuroendocrine malignancies, although our understanding of the function of SEZ6 as a driver of cancer is limited. A lineage-defining transcription factor of SCLC, ASCL1, has been implicated as a regulator of SEZ6 expression. SEZ6 has emerged as a novel target for antibody–drug conjugate therapy, and early studies have shown promising antitumor activity, demonstrating the potential for SEZ6 to be targeted by drugs with alternate mechanisms of action. In this article, we review the current knowledge of the biology of SEZ6 and its implications in malignancy, summarize the preclinical and clinical findings of SEZ6-targeted antibody–drug conjugates, and discuss future directions to further elucidate the role of SEZ6 in SCLC and other neuroendocrine neoplasms.</p>}},
  author       = {{Gezelius, Emelie and Rekhtman, Natasha and Baine, Marina K. and Rudin, Charles M. and Drilon, Alexander and Cooper, Alissa J.}},
  issn         = {{1078-0432}},
  language     = {{eng}},
  month        = {{11}},
  number       = {{21}},
  pages        = {{4419--4428}},
  publisher    = {{American Association for Cancer Research Inc.}},
  series       = {{Clinical Cancer Research}},
  title        = {{Seizure-Related Homolog Protein 6 (SEZ6) : Biology and Therapeutic Target in Neuroendocrine Carcinomas}},
  url          = {{http://dx.doi.org/10.1158/1078-0432.CCR-25-2090}},
  doi          = {{10.1158/1078-0432.CCR-25-2090}},
  volume       = {{31}},
  year         = {{2025}},
}