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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
Volume33
Issue2
Pages202-216.e6
Date Published2018 02 12
ISSN1878-3686
KeywordsCell Line, Tumor, Cell Proliferation, Cyclin-Dependent Kinases, Gene Expression Regulation, Neoplastic, Humans, Oncogene Proteins, Fusion, Phenylenediamines, Proto-Oncogene Protein c-fli-1, Pyrimidines, RNA-Binding Protein EWS, Sarcoma, Ewing, Synthetic Lethal Mutations
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
PubMed Central IDPMC5846483
Grant ListR01 HG002668 / HG / NHGRI NIH HHS / United States
R35 CA210030 / CA / NCI NIH HHS / United States