Title |
Functional, chemical genomic, and super-enhancer screening identify sensitivity to cyclin D1/CDK4 pathway inhibition in Ewing sarcoma
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Published in |
Oncotarget, August 2015
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DOI | 10.18632/oncotarget.4903 |
Pubmed ID | |
Authors |
Alyssa L. Kennedy, Mounica Vallurupalli, Liying Chen, Brian Crompton, Glenn Cowley, Francisca Vazquez, Barbara A. Weir, Aviad Tsherniak, Sudha Parasuraman, Sunkyu Kim, Gabriela Alexe, Kimberly Stegmaier |
Abstract |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
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Unknown | 1 | 100% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 1 | 100% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
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Spain | 1 | 1% |
United States | 1 | 1% |
China | 1 | 1% |
Austria | 1 | 1% |
Unknown | 79 | 95% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 18 | 22% |
Researcher | 14 | 17% |
Student > Bachelor | 6 | 7% |
Student > Master | 5 | 6% |
Student > Doctoral Student | 4 | 5% |
Other | 11 | 13% |
Unknown | 25 | 30% |
Readers by discipline | Count | As % |
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Agricultural and Biological Sciences | 21 | 25% |
Biochemistry, Genetics and Molecular Biology | 16 | 19% |
Medicine and Dentistry | 14 | 17% |
Psychology | 3 | 4% |
Immunology and Microbiology | 2 | 2% |
Other | 1 | 1% |
Unknown | 26 | 31% |