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.
Elizabeth Stewart  1 ,  Justina McEvoy  2 ,  Hong Wang  3 ,  Xiang Chen  4 ,  Victoria Honnell  1 ,  Monica Ocarz  5 ,  Brittney Gordon  5 ,  Jason Dapper  1 ,  Kaley Blankenship  6 ,  Yanling Yang  7 ,  Yuxin Li  8 ,  Timothy I Shaw  9 ,  Ji-Hoon Cho  10 ,  Xusheng Wang  10 ,  Beisi Xu  4 ,  Pankaj Gupta  4 ,  Yiping Fan  4 ,  Yu Liu  4 ,  Michael Rusch  4 ,  Lyra Griffiths  5 ,  Jongrye Jeon  5 ,  Burgess B Freeman 3rd  11 ,  Michael R Clay  12 ,  Alberto Pappo  6 ,  John Easton  4 ,  Sheila Shurtleff  12 ,  Anang Shelat  13 ,  Xin Zhou  4 ,  Kristy Boggs  4 ,  Heather Mulder  4 ,  Donald Yergeau  4 ,  Armita Bahrami  12 ,  Elaine R Mardis  14 ,  Richard K Wilson  15 ,  Jinghui Zhang  4 ,  Junmin Peng  7 ,  James R Downing  12 ,  Michael A Dyer  16 ,  St. Jude Children's Research Hospital – Washington University Pediatric Cancer Genome Project
Affiliations
  • 1. Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, MS 323, Memphis, TN 38105-3678, USA; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 2. Departments of Molecular and Cellular Biology and Pediatrics, BIO5 Institute, University of Arizona, Tucson, AZ 85721, USA.
  • 3. Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Integrated Biomedical Sciences, University of Tennessee Health Science Center, Memphis, TN 38105, USA.
  • 4. Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 5. Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, MS 323, Memphis, TN 38105-3678, USA.
  • 6. Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 7. Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 8. Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Proteomics Shared Resource, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 9. Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Proteomics Shared Resource, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 10. Proteomics Shared Resource, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 11. Preclinical Pharmacokinetics Shared Resource, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 12. Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 13. Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 14. The McDonnell Genome Institute, Washington University, St. Louis, MO 63108, USA; Department of Genetics, Washington University, St. Louis, MO 63108, USA; Department of Medicine, Washington University, St. Louis, MO 63108, USA.
  • 15. The McDonnell Genome Institute, Washington University, St. Louis, MO 63108, USA; Department of Genetics, Washington University, St. Louis, MO 63108, USA; Siteman Cancer Center, Washington University School of Medicine in St. Louis, St. Louis, MO 63108, USA.
  • 16. Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, MS 323, Memphis, TN 38105-3678, USA; Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN 38105, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: [email protected].
PMID: 30146332 DOI: 10.1016/j.ccell.2018.07.012
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.
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