Functional, chemical genomic, and super-enhancer screening identify sensitivity to cyclin D1/CDK4 pathway inhibition in Ewing sarcoma

摘要: // Alyssa L. Kennedy 1, 2, * , Mounica Vallurupalli 3, Liying Chen Brian Crompton 1 Glenn Cowley 4 Francisca Vazquez Barbara A. Weir Aviad Tsherniak Sudha Parasuraman 5 Sunkyu Kim Gabriela Alexe 4, 6 Kimberly Stegmaier Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children’s Hospital, Boston, Massachusetts, USA 2 Combined Residency Program in Pediatrics, 3 Internal Medicine, Brigham Women’s Broad Institute, Cambridge, Novartis for Biomedical Research, Bioinformatics Graduate Program, University, These authors have contributed equally to this work Correspondence to: Stegmaier, e-mail: kimberly_stegmaier@dfci.harvard.edu Keywords: CDK4/6 inhibitor, cyclin D1, epigenetics, Ewing sarcoma, sarcoma/soft-tissue malignancies Received: June 29, 2015      Accepted: August 07, Published: 18, 2015 ABSTRACT sarcoma is an aggressive bone soft tissue tumor children adolescents, with treatment remaining a clinical challenge. This disease mediated by somatic chromosomal translocations the EWS gene encoding ETS transcription factor, most commonly, FLI1 . While direct targeting aberrant factors remains pharmacological challenge, identification dependencies incurred EWS/FLI1 expression would offer new therapeutic avenue. We used combination super-enhancer profiling, near-whole genome shRNA-based small-molecule screening identify D1 CDK4 as sarcoma-selective dependencies. revealed that super-enhancers mark specific signatures target genes human cell lines. Particularly, regulates promotes its sarcoma. demonstrated cells require survival anchorage-independent growth. Additionally, pharmacologic inhibition selective inhibitors led cytostasis death lines vitro growth delay vivo xenograft model. results dependency on support exploration approach patients disease.