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

Amanda Balboni Iniguez; Björn Stolte; Emily Jue Wang; Amy Saur Conway; Gabriela Alexe; Neekesh V Dharia; Nicholas Kwiatkowski; Tinghu Zhang; Brian J Abraham; Jaume Mora; Peter Kalev; Alan Leggett; Dipanjan Chowdhury; Cyril H Benes; Richard A Young; Nathanael S Gray; Kimberly Stegmaier

doi:10.1016/j.ccell.2017.12.009

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

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

Authors

Amanda Balboni Iniguez¹, Björn Stolte², Emily Jue Wang¹, Amy Saur Conway³, Gabriela Alexe⁴, Neekesh V Dharia¹, Nicholas Kwiatkowski⁵, Tinghu Zhang⁶, Brian J Abraham⁷, Jaume Mora⁸, Peter Kalev⁹, Alan Leggett⁶, Dipanjan Chowdhury⁹, Cyril H Benes¹⁰, Richard A Young¹¹, Nathanael S Gray⁶, Kimberly Stegmaier¹²

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
Cell Proliferation / drug effects
Cyclin-Dependent Kinases / drug effects*
Cyclin-Dependent Kinases / genetics
Gene Expression Regulation, Neoplastic / drug effects
Humans
Oncogene Proteins, Fusion / drug effects
Oncogene Proteins, Fusion / genetics
Phenylenediamines / pharmacology*
Proto-Oncogene Protein c-fli-1 / drug effects
Proto-Oncogene Protein c-fli-1 / genetics*
Pyrimidines / pharmacology*
RNA-Binding Protein EWS / drug effects
RNA-Binding Protein EWS / genetics*
Sarcoma, Ewing / genetics*
Synthetic Lethal Mutations / drug effects
Synthetic Lethal Mutations / genetics

Substances

Oncogene Proteins, Fusion
Phenylenediamines
Proto-Oncogene Protein c-fli-1
Pyrimidines
RNA-Binding Protein EWS
THZ1 compound
CDK12 protein, human
Cyclin-Dependent Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding