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• W1989693946 abstract "Background High-risk neuroblastoma is a pediatric cancer that is often fatal despite intense multimodality therapy associated with significant late effects for those who survive. Therefore, patients will benefit from treatment strategies that rationally exploit signaling pathways for which a tumor cell is selectively dependent. In an effort to identify novel therapeutic targets, we performed a comprehensive loss of function screen of the protein kinome in neuroblastoma cell models. Methods Using a validated siRNA library which targets the human protein kinome, we transiently transfected individual kinase siRNAs into four neuroblastoma cell lines and measured substrate adherent growth. We then ranked the top 100 most potent kinase siRNAs per cell line and integrated the lists to identify kinases with inhibition in multiple lines. Results Thirty targets emerged as potent in at least three of the four neuroblastoma cell lines. They were enriched for kinases involved in the cell cycle and mitosis. This select group was tested with an independent set of more specific siRNA pools in an expanded panel of eight neuroblastoma cell lines. The strikingly most potent to emerge from the secondary screen was the cell cycle checkpoint kinase CHEK1. CHEK1 knockdown appeared cytotoxic, often by 24 hours, coinciding with complete CHEK1 protein knockdown and an emergence of a substantial apoptotic fraction. As further validation of the siRNA results, pharmacologic inhibition with SB21807, a relatively specific CHEK1 inhibitor, showed cytotoxicity in 7 of 8 neuroblastoma cell lines with a median IC50 of 430 nM (range 62-677 nM), while the non-neuroblastoma lines RPE-1, DOAY and MCF7 cells were resistant with a median IC50 of 2609 nM (1066 - 2898 nM). The mechanism of selective inhibition in neuroblastoma is unclear as we did not identify mutations in the coding exons of CHEK1. Western blotting revealed, however, that CHEK1 is constitutively phosphorylated at the Ser 296 residue in 8/8 neuroblastoma cell lines and 10/16 primary tumors samples, but not in controls. Conclusion We have identified CHEK1 as a potential therapeutic target in neuroblastoma and are currently extending our work to understand the mechanism of this tumor9s apparent selective sensitivity to CHEK1 inhibition. As CHEK1 inhibitors are currently in phase I/II clinical trials as chemosensitizers, we are also focused on determining the in vivo efficacy of combination CHEK1 inhibition with chemotherapy in neuroblastoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5263." @default.
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• W1989693946 date "2010-04-15" @default.
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• W1989693946 title "Abstract 5263: An RNAi screen of the protein kinome identifiesCHEK1as a therapeutic target in neuroblastoma" @default.
• W1989693946 doi "https://doi.org/10.1158/1538-7445.am10-5263" @default.
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