ASCL1 is a lineage oncogene providing therapeutic targets for high-grade neuroendocrine lung cancers

Alexander Augustyn, Mark Borromeo, Tao Wang, Junya Fujimoto, Chunli Shao, Patrick D. Dospoy, Victoria Lee, Christopher Tan, James P. Sullivan, Jill E. Larsen, Luc Girard, Carmen Behrens, Ignacio I. Wistuba, Yang Xie, Melanie H. Cobb, Adi F. Gazdar, Jane E. Johnson, John D. Minna, Peter K. Vogt

Research output: Contribution to journalArticle

93 Scopus citations

Abstract

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 achaetescute 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 ChIPSeq 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.

Original languageEnglish (US)
Pages (from-to)14788-14793
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number41
DOIs
StatePublished - Oct 14 2014

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Keywords

  • ASCL1 transcriptome
  • Personalized therapy
  • Target discovery

ASJC Scopus subject areas

  • General

Cite this

Augustyn, A., Borromeo, M., Wang, T., Fujimoto, J., Shao, C., Dospoy, P. D., Lee, V., Tan, C., Sullivan, J. P., Larsen, J. E., Girard, L., Behrens, C., Wistuba, I. I., Xie, Y., Cobb, M. H., Gazdar, A. F., Johnson, J. E., Minna, J. D., & Vogt, P. K. (2014). ASCL1 is a lineage oncogene providing therapeutic targets for high-grade neuroendocrine lung cancers. Proceedings of the National Academy of Sciences of the United States of America, 111(41), 14788-14793. https://doi.org/10.1073/pnas.1410419111