CRISPR knockout screening identifies combinatorial drug targets in pancreatic cancer and models cellular drug response

Nat Commun. 2018 Oct 15;9(1):4275. doi: 10.1038/s41467-018-06676-2.


Predicting the response and identifying additional targets that will improve the efficacy of chemotherapy is a major goal in cancer research. Through large-scale in vivo and in vitro CRISPR knockout screens in pancreatic ductal adenocarcinoma cells, we identified genes whose genetic deletion or pharmacologic inhibition synergistically increase the cytotoxicity of MEK signaling inhibitors. Furthermore, we show that CRISPR viability scores combined with basal gene expression levels could model global cellular responses to the drug treatment. We develop drug response evaluation by in vivo CRISPR screening (DREBIC) method and validated its efficacy using large-scale experimental data from independent experiments. Comparative analyses demonstrate that DREBIC predicts drug response in cancer cells from a wide range of tissues with high accuracy and identifies therapeutic vulnerabilities of cancer-causing mutations to MEK inhibitors in various cancer types.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Cell Cycle Checkpoints
  • Cell Death
  • Cell Line, Tumor
  • Clustered Regularly Interspaced Short Palindromic Repeats / genetics*
  • Combinatorial Chemistry Techniques*
  • Drug Delivery Systems*
  • Drug Synergism
  • Gene Knockout Techniques*
  • Genetic Testing*
  • Humans
  • Mice, Nude
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Models, Biological*
  • Pancreatic Neoplasms / genetics*
  • Reproducibility of Results


  • Antineoplastic Agents
  • Mitogen-Activated Protein Kinase Kinases