Functional, chemical genomic, and super-enhancer screening identify sensitivity to cyclin D1/CDK4 pathway inhibition in Ewing sarcoma
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Alyssa L. Kennedy1,2,*, Mounica Vallurupalli1,3,*, Liying Chen1,*, Brian Crompton1, Glenn Cowley4, Francisca Vazquez4, Barbara A. Weir4, Aviad Tsherniak4, Sudha Parasuraman5, Sunkyu Kim5, Gabriela Alexe1,4,6, Kimberly Stegmaier1,4
1Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children’s Hospital, Boston, Massachusetts, USA
2Boston Combined Residency Program in Pediatrics, Boston, Massachusetts, USA
3Department of Internal Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA
4Broad Institute, Cambridge, Massachusetts, USA
5Novartis Institute for Biomedical Research, Cambridge, Massachusetts, USA
6Bioinformatics Graduate Program, Boston University, Boston, Massachusetts, USA
*These authors have contributed equally to this work
Kimberly Stegmaier, e-mail: firstname.lastname@example.org
Keywords: CDK4/6 inhibitor, cyclin D1, epigenetics, Ewing sarcoma, sarcoma/soft-tissue malignancies
Received: June 29, 2015 Accepted: August 07, 2015 Published: August 18, 2015
Ewing sarcoma is an aggressive bone and soft tissue tumor in children and adolescents, with treatment remaining a clinical challenge. This disease is mediated by somatic chromosomal translocations of the EWS gene and a gene encoding an ETS transcription factor, most commonly, FLI1. While direct targeting of aberrant transcription factors remains a pharmacological challenge, identification of dependencies incurred by EWS/FLI1 expression would offer a new therapeutic avenue. We used a combination of super-enhancer profiling, near-whole genome shRNA-based and small-molecule screening to identify cyclin D1 and CDK4 as Ewing sarcoma-selective dependencies. We revealed that super-enhancers mark Ewing sarcoma specific expression signatures and EWS/FLI1 target genes in human Ewing sarcoma cell lines. Particularly, a super-enhancer regulates cyclin D1 and promotes its expression in Ewing sarcoma. We demonstrated that Ewing sarcoma cells require CDK4 and cyclin D1 for survival and anchorage-independent growth. Additionally, pharmacologic inhibition of CDK4 with selective CDK4/6 inhibitors led to cytostasis and cell death of Ewing sarcoma cell lines in vitro and growth delay in an in vivo Ewing sarcoma xenograft model. These results demonstrated a dependency in Ewing sarcoma on CDK4 and cyclin D1 and support exploration of CDK4/6 inhibitors as a therapeutic approach for patients with this disease.
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