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

Seizure-related homolog protein 6 (SEZ6) is a cell surface type 1 transmembrane protein involved in neuronal development, 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’s 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 (ADC) therapy, and early studies have shown promising antitumor activity, demonstrating the potential for SEZ6 to be targeted by drugs with alternate mechanisms of action. Here, we review the current knowledge of the biology of SEZ6 and its implications in malignancy, summarize the preclinical and clinical findings of SEZ6 targeted ADCs, and discuss future directions to further elucidate the role of SEZ6 in SCLC and other neuroendocrine neoplasms.