Universität zu Köln

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

Full text not available from this repository.

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:	Creators Email ORCID ORCID Put Code Dietlein, Felix UNSPECIFIED UNSPECIFIED UNSPECIFIED Thelen, Lisa UNSPECIFIED UNSPECIFIED UNSPECIFIED Jokic, Mladen UNSPECIFIED UNSPECIFIED UNSPECIFIED Jachimowicz, Ron D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ivan, Laura UNSPECIFIED UNSPECIFIED UNSPECIFIED Knittel, Gero UNSPECIFIED UNSPECIFIED UNSPECIFIED Leeser, Uschi UNSPECIFIED UNSPECIFIED UNSPECIFIED van Oers, Johanna UNSPECIFIED UNSPECIFIED UNSPECIFIED Edelmann, Winfried UNSPECIFIED UNSPECIFIED UNSPECIFIED Heukamp, Lukas C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Reinhardt, H. Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED
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:	Keywords Language DNA-DAMAGE RESPONSE; STRAND BREAK REPAIR; ONCOGENE-INDUCED SENESCENCE; HOMOLOGOUS RECOMBINATION; COLORECTAL-CANCER; DRUG-SENSITIVITY; MISMATCH-REPAIR; LUNG-CANCER; CELL-CYCLE; MECHANISMS Multiple languages Oncology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/43988