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J Exp Med DOI:10.1084/jem.20171066

Genome-scale CRISPR-Cas9 screen identifies druggable dependencies in wild-type Ewing sarcoma.

Publication TypeJournal Article
Year of Publication2018
AuthorsStolte, B, Iniguez, ABalboni, Dharia, NV, Robichaud, AL, Conway, ASaur, Morgan, AM, Alexe, G, Schauer, NJ, Liu, X, Bird, GH, Tsherniak, A, Vazquez, F, Buhrlage, SJ, Walensky, LD, Stegmaier, K
JournalJ Exp Med
Volume215
Issue8
Pages2137-2155
Date Published2018 Aug 06
ISSN1540-9538
Abstract

Ewing sarcoma is a pediatric cancer driven by EWS-ETS transcription factor fusion oncoproteins in an otherwise stable genomic background. The majority of tumors express wild-type , and thus, therapies targeting the p53 pathway would benefit most patients. To discover targets specific for wild-type Ewing sarcoma, we used a genome-scale CRISPR-Cas9 screening approach and identified and validated , , and as druggable dependencies. The stapled peptide inhibitor of MDM2 and MDM4, ATSP-7041, showed anti-tumor efficacy in vitro and in multiple mouse models. The USP7 inhibitor, P5091, and the Wip1/ inhibitor, GSK2830371, decreased the viability of Ewing sarcoma cells. The combination of ATSP-7041 with P5091, GSK2830371, and chemotherapeutic agents showed synergistic action on the p53 pathway. The effects of the inhibitors, including the specific USP7 inhibitor XL-188, were rescued by concurrent knockout, highlighting the essentiality of intact p53 for the observed cytotoxic activities.

DOI10.1084/jem.20171066
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/30045945?dopt=Abstract

Alternate JournalJ. Exp. Med.
PubMed ID30045945
PubMed Central IDPMC6080915
Grant ListT32 CA136432 / CA / NCI NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
R35 CA210030 / CA / NCI NIH HHS / United States
F30 CA221087 / CA / NCI NIH HHS / United States
T32 GM008313 / GM / NIGMS NIH HHS / United States
R50 CA211399 / CA / NCI NIH HHS / United States
R01 CA211681 / CA / NCI NIH HHS / United States