RT Journal Article
SR Electronic
T1 Inhibition of a Selective SWI/SNF Function Synergizes with ATR Inhibitors in Cancer Cell Killing
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 660456
DO 10.1101/660456
A1 Emma J. Chory
A1 Jacob G. Kirkland
A1 Chiung-Ying Chang
A1 Vincent D. D’Andrea
A1 Sai Gourinsankar
A1 Emily C. Dykhuizen
A1 Gerald R. Crabtree
YR 2019
UL http://biorxiv.org/content/early/2019/06/04/660456.abstract
AB SWI/SNF (BAF) complexes are a diverse family of ATP-dependent chromatin remodelers produced by combinatorial assembly that are mutated in and thought to contribute to 20% of human cancers and a large number of neurologic diseases. The gene-activating functions of BAF complexes are essential for viability of many cell types, limiting the development of small molecule inhibitors. To circumvent the potential toxicity of SWI/SNF inhibition, we identified small molecules that inhibit the specific repressive function of these complexes but are relatively non-toxic and importantly synergize with ATR inhibitors in killing cancer cells. Our studies suggest an avenue for therapeutic enhancement of ATR/ATM inhibition and provide evidence for chemical synthetic lethality of BAF complexes as a therapeutic strategy in cancer.