Dietlein, Felix, Thelen, Lisa, Jokic, Mladen, Jachimowicz, Ron D., Ivan, Laura, Knittel, Gero, Leeser, Uschi, van Oers, Johanna, Edelmann, Winfried, Heukamp, Lukas C. and Reinhardt, H. Christian (2014). A Functional Cancer Genomics Screen Identifies a Druggable Synthetic Lethal Interaction between MSH3 and PRKDC. Cancer Discov., 4 (5). S. 592 - 606. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 2159-8290

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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 (similar to 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. (C) 2014 AACR.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Dietlein, FelixUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thelen, LisaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jokic, MladenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jachimowicz, Ron D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ivan, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Knittel, GeroUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Leeser, UschiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Oers, JohannaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Edelmann, WinfriedUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heukamp, Lukas C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reinhardt, H. ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-439882
DOI: 10.1158/2159-8290.CD-13-0907
Journal or Publication Title: Cancer Discov.
Volume: 4
Number: 5
Page Range: S. 592 - 606
Date: 2014
Publisher: AMER ASSOC CANCER RESEARCH
Place of Publication: PHILADELPHIA
ISSN: 2159-8290
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
DNA-DAMAGE RESPONSE; STRAND BREAK REPAIR; ONCOGENE-INDUCED SENESCENCE; HOMOLOGOUS RECOMBINATION; COLORECTAL-CANCER; DRUG-SENSITIVITY; MISMATCH-REPAIR; LUNG-CANCER; CELL-CYCLE; MECHANISMSMultiple languages
OncologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/43988

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