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

J Exp Med
Authors
Keywords
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.

Year of Publication
2018
Journal
J Exp Med
Volume
215
Issue
8
Pages
2137-2155
Date Published
2018 08 06
ISSN
1540-9538
DOI
10.1084/jem.20171066
PubMed ID
30045945
PubMed Central ID
PMC6080915
Links
Grant list
T32 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
R35 CA197583 / CA / NCI NIH HHS / United States
R50 CA211399 / CA / NCI NIH HHS / United States
R01 CA211681 / CA / NCI NIH HHS / United States