文章基本信息

标题：ASCL1 is a lineage oncogene providing therapeutic targets for high-grade neuroendocrine lung cancers
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作者：Alexander Augustyn ; Mark Borromeo ; Tao Wang 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2014
卷号：111
期号：41
页码：14788-14793
DOI：10.1073/pnas.1410419111
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceNew advances in the treatment of aggressive neuroendocrine lung cancers are needed to improve survival in patients with this class of tumors. The current treatment approach, which has remained unchanged for the past 30 years, involves combination chemotherapy and radiation. To uncover novel drug targets, we identified the transcriptome of achaete-scute homolog 1 (ASCL1), a transcription factor that is both necessary for the proper development of neuroendocrine cells and essential for the growth and survival of neuroendocrine lung cancers. Analysis of downstream targets of ASCL1 has revealed unique molecular vulnerabilities that can be exploited for future therapeutic use. Aggressive neuroendocrine lung cancers, including small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), represent an understudied tumor subset that accounts for approximately 40,000 new lung cancer cases per year in the United States. No targeted therapy exists for these tumors. We determined that achaete-scute homolog 1 (ASCL1), a transcription factor required for proper development of pulmonary neuroendocrine cells, is essential for the survival of a majority of lung cancers (both SCLC and NSCLC) with neuroendocrine features. By combining whole-genome microarray expression analysis performed on lung cancer cell lines with ChIP-Seq data designed to identify conserved transcriptional targets of ASCL1, we discovered an ASCL1 target 72-gene expression signature that (i) identifies neuroendocrine differentiation in NSCLC cell lines, (ii) is predictive of poor prognosis in resected NSCLC specimens from three datasets, and (iii) represents novel "druggable" targets. Among these druggable targets is B-cell CLL/lymphoma 2, which when pharmacologically inhibited stops ASCL1-dependent tumor growth in vitro and in vivo and represents a proof-of-principle ASCL1 downstream target gene. Analysis of downstream targets of ASCL1 represents an important advance in the development of targeted therapy for the neuroendocrine class of lung cancers, providing a significant step forward in the understanding and therapeutic targeting of the molecular vulnerabilities of neuroendocrine lung cancer.
关键词：ASCL1 transcriptome ; target discovery ; personalized therapy