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Cancer Cell. 2018 Feb 12;33(2):202-216.e6. doi: 10.1016/j.ccell.2017.12.009. Epub 2018 Jan 18.

EWS/FLI Confers Tumor Cell Synthetic Lethality to CDK12 Inhibition in Ewing Sarcoma.

Author information

1
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
2
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA; Ludwig Maximilians University of Munich, Munich 80539, Germany.
3
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA.
4
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Bioinformatics Graduate Program, Boston University, Boston, MA 02215, USA.
5
The Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
6
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
7
The Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
8
Development Tumor Biology Laboratory and Department of Pediatric Oncology and Hematology, Hospital Sant Joan de Déu Barcelona, Barcelona 08950, Spain.
9
Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
10
Massachusetts General Hospital, Center for Cancer Research, Boston, MA 02114, USA.
11
The Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
12
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: kimberly_stegmaier@dfci.harvard.edu.

Abstract

Many cancer types are driven by oncogenic transcription factors that have been difficult to drug. Transcriptional inhibitors, however, may offer inroads into targeting these cancers. Through chemical genomics screening, we identified that Ewing sarcoma is a disease with preferential sensitivity to THZ1, a covalent small-molecule CDK7/12/13 inhibitor. The selective CDK12/13 inhibitor, THZ531, impairs DNA damage repair in an EWS/FLI-dependent manner, supporting a synthetic lethal relationship between response to THZ1/THZ531 and EWS/FLI expression. The combination of these molecules with PARP inhibitors showed striking synergy in cell viability and DNA damage assays in vitro and in multiple models of Ewing sarcoma, including a PDX, in vivo without hematopoietic toxicity.

KEYWORDS:

CDK12; DNA damage repair; EWS/FLI; Ewing sarcoma; PARP inhibitors; THZ1; THZ531; synthetic lethal

PMID:
29358035
PMCID:
PMC5846483
DOI:
10.1016/j.ccell.2017.12.009
[Indexed for MEDLINE]
Free PMC Article

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