Identification of Therapeutic Targets in Rhabdomyosarcoma through Integrated Genomic, Epigenomic, and Proteomic Analyses

St. Jude Children's Research Hospital – Washington University Pediatric Cancer Genome Project

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

Personalized cancer therapy targeting somatic mutations in patient tumors is increasingly being incorporated into practice. Other therapeutic vulnerabilities resulting from changes in gene expression due to tumor specific epigenetic perturbations are progressively being recognized. These genomic and epigenomic changes are ultimately manifest in the tumor proteome and phosphoproteome. We integrated transcriptomic, epigenomic, and proteomic/phosphoproteomic data to elucidate the cellular origins and therapeutic vulnerabilities of rhabdomyosarcoma (RMS). We discovered that alveolar RMS occurs further along the developmental program than embryonal RMS. We also identified deregulation of the RAS/MEK/ERK/CDK4/6, G2/M, and unfolded protein response pathways through our integrated analysis. Comprehensive preclinical testing revealed that targeting the WEE1 kinase in the G2/M pathway is the most effective approach in vivo for high-risk RMS. Using integrated analyses, Stewart et al. reveal the developmental origin of rhabdomyosarcoma (RMS) and identify commonly deregulated pathways. Comprehensive preclinical testing helps prioritize agents for future clinical trials and shows WEE1 as a highly effective therapeutic target for high-risk RMS in vivo.

Original languageEnglish (US)
Pages (from-to)411-426.e19
JournalCancer Cell
Volume34
Issue number3
DOIs
StatePublished - Sep 10 2018

Keywords

  • epigenetics
  • molecular targeted therapy
  • pediatric cancer
  • preclinical testing
  • proteomics
  • rhabdomyosarcoma

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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