EWS/FLI Confers Tumor Cell Synthetic Lethality to CDK12 Inhibition in Ewing Sarcoma
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nihms935677.pdf
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Author(s)
Iniguez, Amanda Balboni
Stolte, Björn
Wang, Emily Jue
Conway, Amy Saur
Alexe, Gabriela
Dharia, Neekesh V.
Kwiatkowski, Nicholas
Zhang, Tinghu
Abraham, Brian J.
Mora, Jaume
Date Issued
February 2018
Journal
Cancer Cell
Publisher
Elsevier BV
Citation
Iniguez, Amanda Balboni, Björn Stolte, Emily Jue Wang, Amy Saur Conway, Gabriela Alexe, Neekesh V. Dharia, Nicholas Kwiatkowski, et al. “EWS/FLI Confers Tumor Cell Synthetic Lethality to CDK12 Inhibition in Ewing Sarcoma.” Cancer Cell 33, no. 2 (February 2018): 202–216.e6. © 2017 Elsevier Inc.
Version
Final published version
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. Iniguez et al. find that inhibition of CDK12 is synthetic lethal with EWS/FLI expression. CDK12/13 inhibitors impair DNA damage repair in cells expressing EWS/FLI, and the combination of CDK12/13 and PARP inhibitors synergistically reduces tumor growth and extends survival in Ewing sarcoma mouse models.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Whitehead Institute for Biomedical Research
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Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1016/J.CCELL.2017.12.009
