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

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

Cancer cell (2018-01-24)

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

PMID29358035

摘要

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.