Genome-scale CRISPR-Cas9 screen identifies druggable dependencies in TP53 wild-type Ewing sarcoma.

Autor:	Stolte B; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, MA.; Dr. von Hauner Children's Hospital, Department of Pediatrics, University Hospital, LMU Munich, Munich, Germany.; The Broad Institute of MIT and Harvard, Cambridge, MA., Iniguez AB; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, MA.; The Broad Institute of MIT and Harvard, Cambridge, MA., Dharia NV; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, MA.; The Broad Institute of MIT and Harvard, Cambridge, MA., Robichaud AL; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, MA., Conway AS; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, MA., Morgan AM; Department of Pediatric Oncology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA., Alexe G; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, MA.; The Broad Institute of MIT and Harvard, Cambridge, MA.; Bioinformatics Graduate Program, Boston University, Boston, MA., Schauer NJ; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA., Liu X; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA., Bird GH; Department of Pediatric Oncology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA., Tsherniak A; The Broad Institute of MIT and Harvard, Cambridge, MA., Vazquez F; The Broad Institute of MIT and Harvard, Cambridge, MA., Buhrlage SJ; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA., Walensky LD; Department of Pediatric Oncology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA loren_walensky@dfci.harvard.edu., Stegmaier K; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, MA kimberly_stegmaier@dfci.harvard.edu.; The Broad Institute of MIT and Harvard, Cambridge, MA.
Jazyk:	angličtina
Zdroj:	The Journal of experimental medicine [J Exp Med] 2018 Aug 06; Vol. 215 (8), pp. 2137-2155. Date of Electronic Publication: 2018 Jul 25.
DOI:	10.1084/jem.20171066
Abstrakt:	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. (© 2018 Stolte et al.)
Databáze:	MEDLINE
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