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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 111; no. 41; pp. 14788 - 14793
• Main Authors: Augustyn, Alexander, Borromeo, Mark, Wang, Tao, Fujimoto, Junya, Shao, Chunii, Dospoy, Patrick D., Lee, Victoria, Tan, Christopher, Sullivan, James P., Larsen, Jill E., Girard, Luc, Behrens, Carmen, Wistuba, Ignacio I., Xie, Yang, Cobb, Melanie H., Gazdar, Adi F., Johnson, Jane E., Minna, John D.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 14.10.2014; National Acad Sciences
• Subjects: Adenocarcinoma; Adenocarcinoma - genetics; Adenocarcinoma - pathology; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Biological Sciences; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Cell Line, Tumor; Cell Lineage; Cell lines; Cell Survival; Chromatin Immunoprecipitation; drug therapy; drugs; Gene expression; Gene Expression Regulation, Neoplastic; Genes; Humans; Immunohistochemistry; Lung cancer; Lung neoplasms; Lungs; Lymphoma; Medical treatment; Messenger RNA; Neuroendocrine Tumors - genetics; Neuroendocrine Tumors - pathology; Neurons; Oncogenes; Oncology; patients; Prognosis; Proto-Oncogene Proteins c-bcl-2 - metabolism; Signatures; Small cell lung carcinoma; Small Cell Lung Carcinoma - genetics; Small Cell Lung Carcinoma - pathology; transcription factors; transcriptome; Tumors; United States > US; target discovery; ASCL1 transcriptome; personalized therapy
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1410419111

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 ChlP-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.