title: A functional cancer genomics screen identifies a druggable synthetic lethal interaction between MSH3 and PRKDC.
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.
authors.affiliation: 1Department of Translational Genomics; 2Institute of Pathology; 3Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne; 4Department of Internal Medicine, University Hospital of Cologne, Cologne, Germany; and 5Michael F. Price Center, Albert Einstein College of Medicine, Bronx, New York.
authors.forename: Felix
authors.initials: F
authors.lastname: Dietlein
authors.forename: Lisa
authors.initials: L
authors.lastname: Thelen
authors.forename: Mladen
authors.initials: M
authors.lastname: Jokic
authors.forename: Ron D
authors.initials: RD
authors.lastname: Jachimowicz
authors.forename: Laura
authors.initials: L
authors.lastname: Ivan
authors.forename: Gero
authors.initials: G
authors.lastname: Knittel
authors.forename: Uschi
authors.initials: U
authors.lastname: Leeser
authors.forename: Johanna
authors.initials: J
authors.lastname: van Oers
authors.forename: Winfried
authors.initials: W
authors.lastname: Edelmann
authors.forename: Lukas C
authors.initials: LC
authors.lastname: Heukamp
authors.forename: H Christian
authors.initials: HC
authors.lastname: Reinhardt
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051747:DNA-Activated Protein Kinase / Q000037:antagonists & inhibitors* / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D015894:Genome, Human; D006801:Humans; D008297:Male; D051379:Mice; D000074081:MutS Homolog 3 Protein; D009154:Mutation; D009374:Neoplasms, Experimental; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D004268:DNA-Binding Proteins; C078444:MSH3 protein, human; D000074081:MutS Homolog 3 Protein; D009687:Nuclear Proteins; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human