期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 215, 期 8, 页码 2137-2155出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20171066
关键词
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资金
- DAAD (Deutscher Akademischer Austauschdienst) fellowship in the thematic network Research for Rare Diseases and Personalized Medicine
- Damon Runyon Cancer Research Foundation [DRSG-12-15]
- National Institutes of Health (NIH) [T32 CA136432]
- NIH [F30 CA221087, T32 GM007753, T32 GM008313, R50 CA211399, R01 CA211681]
- Quantum Award from Hyundai Hope on Wheels
- REACH grant from the Alex's Lemonade Stand Foundation
- Leukemia and Lymphoma Society
- Brian MacIsaac Sarcoma Foundation
- St. Baldrick's Foundation Robert J. Arceci Innovation Award
- National Cancer Institute [R35 CA210030]
- Cubans Curing Children's Cancers (4C's Fund)
- NATIONAL CANCER INSTITUTE [R01CA211681, R50CA211399, R35CA210030, T32CA136432, F30CA221087, R35CA197583] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM007753, T32GM008313] Funding Source: NIH RePORTER
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 TP53, and thus, therapies targeting the p53 pathway would benefit most patients. To discover targets specific for TP53 wild-type Ewing sarcoma, we used a genome-scale CRISPR-Cas9 screening approach and identified and validated MDM2, MDM4, USP7, and PPM1D 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/PPM1D 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 TP53 knockout, highlighting the essentiality of intact p53 for the observed cytotoxic activities.
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