You are here

Cancer Cell DOI:10.1016/j.ccell.2017.12.009

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

Publication TypeJournal Article
Year of Publication2018
AuthorsIniguez, ABalboni, Stolte, B, Wang, EJue, Conway, ASaur, Alexe, G, Dharia, NV, Kwiatkowski, N, Zhang, T, Abraham, BJ, Mora, J, Kalev, P, Leggett, A, Chowdhury, D, Benes, CH, Young, RA, Gray, NS, Stegmaier, K
JournalCancer Cell
Date Published2018 Jan 17
ISSN1878-3686
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.

DOI10.1016/j.ccell.2017.12.009
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/29358035?dopt=Abstract

Alternate JournalCancer Cell
PubMed ID29358035