RNAi phenotype profiling of kinases identifies potential therapeutic targets in Ewing's sarcoma

Molecular Cancer

Research

Raoul Tibes¹  Chao Sima²  Christian Beaudry³  Ashish Choudhary³  Spyro Mousses³  Shilpi Arora⁴  David O Azorsa⁵  R Tanner Hagelstrom⁵  Irma M Gonzales⁵ 

[1] Clinical Translational Research Division, The Translational Genomics Research Institute, 85259, Scottsdale, Arizona, USA;Computational Biology Division, Translational Genomics Research Institute, 85004, Phoenix, AZ, USA;Pharmaceutical Genomic Division, Translational Genomics Research Institute, 85259, Scottsdale, AZ, USA;Pharmaceutical Genomic Division, Translational Genomics Research Institute, 85259, Scottsdale, AZ, USA;Cancer and Cell Biology Division, Translational Genomics Research Institute, 85004, Phoenix, AZ, USA;Pharmaceutical Genomic Division, Translational Genomics Research Institute, 85259, Scottsdale, AZ, USA;Clinical Translational Research Division, The Translational Genomics Research Institute, 85259, Scottsdale, Arizona, USA;

关键词: Vandetanib;    Phenotypic Profile;    Gene STK10;    Mesoblastic Nephroma;    siRNA Library;   

DOI  :  10.1186/1476-4598-9-218

 received in 2010-03-24, accepted in 2010-08-18,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundEwing'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.ResultsFour 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.ConclusionIn 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.

【 授权许可】

Unknown   
© Arora et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.