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Interhemispheric gamma synchrony between parvalbumin interneurons supports behavioral adaptation

Authors :
Jesse D. Marshall
Thomas J. Davidson
Kathleen K. A. Cho
Vikaas S. Sohal
Mark J. Schnitzer
Publication Year :
2019
Publisher :
Cold Spring Harbor Laboratory, 2019.

Abstract

Here, we use a large-scale cell line–based approach to identify cancer cell–specific mutations that are associated with DNA-dependent protein kinase catalytic subunit (DNA-PKcs) dependence. For this purpose, we profiled the mutational landscape across 1,319 cancer-associated genes of 67 distinct cell lines and identified numerous genes involved in homologous recombination–mediated DNA repair, including BRCA1, BRCA2, ATM, PAXIP, and RAD50, as being associated with non-oncogene addiction to DNA-PKcs. Mutations in the mismatch repair gene MSH3, which have been reported to occur recurrently in numerous human cancer entities, emerged as the most significant predictors of DNA-PKcs addiction. Concordantly, DNA-PKcs inhibition robustly induced apoptosis in MSH3-mutant cell lines in vitro and displayed remarkable single-agent efficacy against MSH3-mutant tumors in vivo. Thus, we here identify a therapeutically actionable synthetic lethal interaction between MSH3 and the non-homologous end joining kinase DNA-PKcs. Our observations recommend DNA-PKcs inhibition as a therapeutic concept for the treatment of human cancers displaying homologous recombination defects. Significance: We associate mutations in the MSH3 gene, which are frequently detected in microsatellite-instable colon cancer (∼40%), with a therapeutic response to specific DNA-PKcs inhibitors. Because potent DNA-PKcs inhibitors are currently entering early clinical trials, we offer a novel opportunity to genetically stratify patients who may benefit from a DNA-PKcs–inhibitory therapy. Cancer Discov; 4(5); 592–605. ©2014 AACR. See related commentary by Hemann, p. 516 This article is highlighted in the In This Issue feature, p. 495

Details

Language :
English
Database :
OpenAIRE
Accession number :
edsair.doi.dedup.....16db8abdfb2ac12e8c34c4f2b09431d9
Full Text :
https://doi.org/10.1101/784330