| Literature DB >> 29358035 |
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.
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.Entities:
Keywords: CDK12; DNA damage repair; EWS/FLI; Ewing sarcoma; PARP inhibitors; THZ1; THZ531; synthetic lethal
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Year: 2018 PMID： 29358035 PMCID： PMC5846483 DOI： 10.1016/j.ccell.2017.12.009
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743