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Methods for Evaluating the Role of c-Fos and Dusp1 in Oncogene Dependence
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Published on: January 7, 2019

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

Alyssa L Kennedy1,2, Mounica Vallurupalli1,3, Liying Chen1

  • 1Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, Massachusetts, USA.

Oncotarget
|September 5, 2015
PubMed

Insights

Researchers identified cyclin D1 and CDK4 as key dependencies in Ewing sarcoma, an aggressive childhood cancer. Targeting CDK4 with inhibitors shows promise for treating this challenging disease.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Ewing sarcoma is a rare, aggressive bone and soft tissue cancer primarily affecting children and adolescents.
  • Current treatments for Ewing sarcoma face significant challenges, highlighting the need for novel therapeutic strategies.
  • The disease is characterized by specific chromosomal translocations involving the EWS gene and ETS transcription factors, most commonly FLI1.

Purpose of the Study:

  • To identify novel therapeutic targets and dependencies in Ewing sarcoma.
  • To investigate the role of super-enhancers in regulating Ewing sarcoma-specific gene expression.
  • To evaluate the therapeutic potential of targeting CDK4 in Ewing sarcoma.

Main Methods:

  • Utilized super-enhancer profiling to identify Ewing sarcoma-specific expression signatures.
  • Conducted genome-wide shRNA and small-molecule screening to uncover cellular dependencies.
  • Employed selective CDK4/6 inhibitors for in vitro and in vivo studies.

Main Results:

  • Identified cyclin D1 and CDK4 as Ewing sarcoma-selective dependencies.
  • Demonstrated that super-enhancers regulate cyclin D1 expression in Ewing sarcoma cells.
  • Showed that Ewing sarcoma cells require CDK4 and cyclin D1 for survival and growth.
  • Pharmacologic inhibition of CDK4 induced cell death and growth delay in preclinical models.

Conclusions:

  • Ewing sarcoma is dependent on CDK4 and cyclin D1 for its survival and proliferation.
  • Targeting CDK4/6 represents a promising therapeutic strategy for Ewing sarcoma.
  • Super-enhancer profiling can identify critical dependencies in cancer.
Keywords:
CDK4/6 inhibitorEwing sarcomacyclin D1epigeneticssarcoma/soft-tissue malignancies

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