title: RNAi phenotype profiling of kinases identifies potential therapeutic targets in Ewing's sarcoma.
abstract: BACKGROUND
  Ewing's sarcomas are aggressive musculoskeletal tumors occurring most frequently in the long and flat bones as a solitary lesion mostly during the teen-age years of life. With current treatments, significant number of patients relapse and survival is poor for those with metastatic disease. As part of novel target discovery in Ewing's sarcoma, we applied RNAi mediated phenotypic profiling to identify kinase targets involved in growth and survival of Ewing's sarcoma cells.
  
  
  RESULTS
  Four Ewing's sarcoma cell lines TC-32, TC-71, SK-ES-1 and RD-ES were tested in high throughput-RNAi screens using a siRNA library targeting 572 kinases. Knockdown of 25 siRNAs reduced the growth of all four Ewing's sarcoma cell lines in replicate screens. Of these, 16 siRNA were specific and reduced proliferation of Ewing's sarcoma cells as compared to normal fibroblasts. Secondary validation and preliminary mechanistic studies highlighted the kinases STK10 and TNK2 as having important roles in growth and survival of Ewing's sarcoma cells. Furthermore, knockdown of STK10 and TNK2 by siRNA showed increased apoptosis.
  
  
  CONCLUSIONS
  In summary, RNAi-based phenotypic profiling proved to be a powerful gene target discovery strategy, leading to successful identification and validation of STK10 and TNK2 as two novel potential therapeutic targets for Ewing's sarcoma.
authors: Pharmaceutical Genomic Division, Translational Genomics Research Institute, Scottsdale, AZ 85259, USA.
authors: Shilpi
authors: S
authors: Arora
authors: Irma M
authors: IM
authors: Gonzales
authors: R Tanner
authors: RT
authors: Hagelstrom
authors: Christian
authors: C
authors: Beaudry
authors: Ashish
authors: A
authors: Choudhary
authors: Chao
authors: C
authors: Sima
authors: Raoul
authors: R
authors: Tibes
authors: Spyro
authors: S
authors: Mousses
authors: David O
authors: DO
authors: Azorsa
mesh_terms: D002455:Cell Division; D045744:Cell Line, Tumor; D006801:Humans; D010641:Phenotype; D034622:RNA Interference; D034741:RNA, Small Interfering; D012512:Sarcoma, Ewing / Q000188:drug therapy* / Q000473:pathology
chemical_list: D034741:RNA, Small Interfering