title: ASCL1 is a lineage oncogene providing therapeutic targets for high-grade neuroendocrine lung cancers.
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 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.
authors.affiliation: Hamon Center for Therapeutic Oncology Research, Simmons Comprehensive Cancer Center, and.
authors.forename: Alexander
authors.initials: A
authors.lastname: Augustyn
authors.affiliation: Departments of Neuroscience.
authors.forename: Mark
authors.initials: M
authors.lastname: Borromeo
authors.affiliation: Simmons Comprehensive Cancer Center, and Clinical Sciences.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Departments of Thoracic/Head and Neck Medical Oncology and Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030;
authors.forename: Junya
authors.initials: J
authors.lastname: Fujimoto
authors.affiliation: Hamon Center for Therapeutic Oncology Research, Simmons Comprehensive Cancer Center, and.
authors.forename: Chunli
authors.initials: C
authors.lastname: Shao
authors.affiliation: Hamon Center for Therapeutic Oncology Research, Simmons Comprehensive Cancer Center, and.
authors.forename: Patrick D
authors.initials: PD
authors.lastname: Dospoy
authors.affiliation: Hamon Center for Therapeutic Oncology Research.
authors.forename: Victoria
authors.initials: V
authors.lastname: Lee
authors.affiliation: Hamon Center for Therapeutic Oncology Research.
authors.forename: Christopher
authors.initials: C
authors.lastname: Tan
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114; and.
authors.forename: James P
authors.initials: JP
authors.lastname: Sullivan
authors.affiliation: Oncogenomics Laboratory, QIMR Berghofer Medical Research Institute, Herston, Brisbane, QLD 4006, Australia.
authors.forename: Jill E
authors.initials: JE
authors.lastname: Larsen
authors.affiliation: Hamon Center for Therapeutic Oncology Research, Simmons Comprehensive Cancer Center, and Pharmacology.
authors.forename: Luc
authors.initials: L
authors.lastname: Girard
authors.affiliation: Departments of Thoracic/Head and Neck Medical Oncology and Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030;
authors.forename: Carmen
authors.initials: C
authors.lastname: Behrens
authors.affiliation: Departments of Thoracic/Head and Neck Medical Oncology and Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030;
authors.forename: Ignacio I
authors.initials: II
authors.lastname: Wistuba
authors.affiliation: Simmons Comprehensive Cancer Center, and Clinical Sciences.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Simmons Comprehensive Cancer Center, and Pharmacology.
authors.forename: Melanie H
authors.initials: MH
authors.lastname: Cobb
authors.affiliation: Hamon Center for Therapeutic Oncology Research, Simmons Comprehensive Cancer Center, and Pathology, and.
authors.forename: Adi F
authors.initials: AF
authors.lastname: Gazdar
authors.affiliation: Departments of Neuroscience, Pharmacology.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Johnson
authors.affiliation: Hamon Center for Therapeutic Oncology Research, Simmons Comprehensive Cancer Center, and Pharmacology, Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75235; john.minna@utsouthwestern.edu.
authors.forename: John D
authors.initials: JD
authors.lastname: Minna
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D019070:Cell Lineage; D002470:Cell Survival; D047369:Chromatin Immunoprecipitation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D018358:Neuroendocrine Tumors / Q000235:genetics* / Q000473:pathology; D009857:Oncogenes; D011379:Prognosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D055752:Small Cell Lung Carcinoma / Q000235:genetics* / Q000473:pathology
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C065500:ASCL1 protein, human
keywords: ASCL1 transcriptome; personalized therapy; target discovery