A functional cancer genomics screen identifies a druggable synthetic lethal interaction between MSH3 and PRKDC

Cancer Discov. 2014 May;4(5):592-605. doi: 10.1158/2159-8290.CD-13-0907. Epub 2014 Feb 20.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / pathology
  • DNA-Activated Protein Kinase / antagonists & inhibitors*
  • DNA-Activated Protein Kinase / genetics*
  • DNA-Binding Proteins / genetics*
  • Genome, Human
  • Humans
  • Male
  • Mice
  • MutS Homolog 3 Protein
  • Mutation
  • Neoplasms, Experimental
  • Nuclear Proteins / antagonists & inhibitors*
  • Nuclear Proteins / genetics*
  • Xenograft Model Antitumor Assays


  • DNA-Binding Proteins
  • MSH3 protein, human
  • MutS Homolog 3 Protein
  • Nuclear Proteins
  • DNA-Activated Protein Kinase
  • PRKDC protein, human