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Interhemispheric gamma synchrony between parvalbumin interneurons supports behavioral adaptation
- 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
- Subjects :
- 0303 health sciences
Kinase
DNA repair
Cancer
Biology
medicine.disease
3. Good health
enzymes and coenzymes (carbohydrates)
03 medical and health sciences
0302 clinical medicine
MSH3
Rad50
Cancer research
medicine
DNA mismatch repair
biological phenomena, cell phenomena, and immunity
Homologous recombination
Gene
030217 neurology & neurosurgery
030304 developmental biology
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....16db8abdfb2ac12e8c34c4f2b09431d9
- Full Text :
- https://doi.org/10.1101/784330