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

Cancer Cell. 2018 Sep 10;34(3):411-426.e19. doi: 10.1016/j.ccell.2018.07.012. Epub 2018 Aug 23.

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.

Keywords: epigenetics; molecular targeted therapy; pediatric cancer; preclinical testing; proteomics; rhabdomyosarcoma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Biomarkers, Tumor / antagonists & inhibitors*
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • Cell Cycle Proteins / antagonists & inhibitors*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Child
  • Epigenomics
  • Female
  • G2 Phase Cell Cycle Checkpoints / drug effects
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / genetics
  • Genomics
  • Humans
  • Male
  • Mice
  • Molecular Targeted Therapy / methods
  • Muscle Neoplasms / drug therapy*
  • Muscle Neoplasms / genetics
  • Muscle Neoplasms / pathology
  • Nuclear Proteins / antagonists & inhibitors*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Precision Medicine / methods
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism
  • Proteomics
  • Rhabdomyosarcoma / drug therapy*
  • Rhabdomyosarcoma / genetics
  • Rhabdomyosarcoma / pathology
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Unfolded Protein Response / genetics
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Biomarkers, Tumor
  • Cell Cycle Proteins
  • Nuclear Proteins
  • Protein-Tyrosine Kinases
  • WEE1 protein, human