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

Shilpi Arora, Irma M. Gonzales, R. T. Hagelstrom, Christian Beaudry, Ashish Choudhary, Chao Sima, Raoul Tibes, Spyro Mousses, David O. Azorsa

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.Conclusion: 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.

Original languageEnglish (US)
Article number218
JournalMolecular Cancer
Volume9
DOIs
StatePublished - Aug 18 2010
Externally publishedYes

Fingerprint

Ewing's Sarcoma
RNA Interference
Phosphotransferases
Phenotype
Small Interfering RNA
Therapeutics
Survival
Growth
Cell Line
Genetic Association Studies
Fibroblasts
Apoptosis
Bone and Bones
Recurrence

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Medicine
  • Oncology

Cite this

Arora, S., Gonzales, I. M., Hagelstrom, R. T., Beaudry, C., Choudhary, A., Sima, C., ... Azorsa, D. O. (2010). RNAi phenotype profiling of kinases identifies potential therapeutic targets in Ewing's sarcoma. Molecular Cancer, 9, [218]. https://doi.org/10.1186/1476-4598-9-218

RNAi phenotype profiling of kinases identifies potential therapeutic targets in Ewing's sarcoma. / Arora, Shilpi; Gonzales, Irma M.; Hagelstrom, R. T.; Beaudry, Christian; Choudhary, Ashish; Sima, Chao; Tibes, Raoul; Mousses, Spyro; Azorsa, David O.

In: Molecular Cancer, Vol. 9, 218, 18.08.2010.

Research output: Contribution to journalArticle

Arora, S, Gonzales, IM, Hagelstrom, RT, Beaudry, C, Choudhary, A, Sima, C, Tibes, R, Mousses, S & Azorsa, DO 2010, 'RNAi phenotype profiling of kinases identifies potential therapeutic targets in Ewing's sarcoma', Molecular Cancer, vol. 9, 218. https://doi.org/10.1186/1476-4598-9-218
Arora, Shilpi ; Gonzales, Irma M. ; Hagelstrom, R. T. ; Beaudry, Christian ; Choudhary, Ashish ; Sima, Chao ; Tibes, Raoul ; Mousses, Spyro ; Azorsa, David O. / RNAi phenotype profiling of kinases identifies potential therapeutic targets in Ewing's sarcoma. In: Molecular Cancer. 2010 ; Vol. 9.
@article{b21247745c4f4584b3f0d40dc8ca7485,
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.Conclusion: 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.",
author = "Shilpi Arora and Gonzales, {Irma M.} and Hagelstrom, {R. T.} and Christian Beaudry and Ashish Choudhary and Chao Sima and Raoul Tibes and Spyro Mousses and Azorsa, {David O.}",
year = "2010",
month = "8",
day = "18",
doi = "10.1186/1476-4598-9-218",
language = "English (US)",
volume = "9",
journal = "Molecular Cancer",
issn = "1476-4598",
publisher = "BioMed Central",

}

TY - JOUR

T1 - RNAi phenotype profiling of kinases identifies potential therapeutic targets in Ewing's sarcoma

AU - Arora, Shilpi

AU - Gonzales, Irma M.

AU - Hagelstrom, R. T.

AU - Beaudry, Christian

AU - Choudhary, Ashish

AU - Sima, Chao

AU - Tibes, Raoul

AU - Mousses, Spyro

AU - Azorsa, David O.

PY - 2010/8/18

Y1 - 2010/8/18

N2 - 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.Conclusion: 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.

AB - 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.Conclusion: 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.

UR - http://www.scopus.com/inward/record.url?scp=77955603620&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77955603620&partnerID=8YFLogxK

U2 - 10.1186/1476-4598-9-218

DO - 10.1186/1476-4598-9-218

M3 - Article

C2 - 20718987

AN - SCOPUS:77955603620

VL - 9

JO - Molecular Cancer

JF - Molecular Cancer

SN - 1476-4598

M1 - 218

ER -