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

Karol Szlachta, Cem Kuscu, Turan Tufan, Sara J. Adair, Stephen Shang, Alex D. Michaels, Matthew G. Mullen, Natasha Lopes Fischer, Jiekun Yang, Limin Liu, Prasad Trivedi, Edward B. Stelow, P. Todd Stukenberg, J. Thomas Parsons, Todd W. Bauer, Mazhar Adli

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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.

Original languageEnglish (US)
Article number4275
JournalNature Communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

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Clustered Regularly Interspaced Short Palindromic Repeats
Pancreatic Neoplasms
Screening
drugs
screening
cancer
Drug Evaluation
Mitogen-Activated Protein Kinase Kinases
Pharmaceutical Preparations
Neoplasms
inhibitors
Drug therapy
Preclinical Drug Evaluations
Chemotherapy
Cytotoxicity
deletion
Gene expression
vulnerability
evaluation
gene expression

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

CRISPR knockout screening identifies combinatorial drug targets in pancreatic cancer and models cellular drug response. / Szlachta, Karol; Kuscu, Cem; Tufan, Turan; Adair, Sara J.; Shang, Stephen; Michaels, Alex D.; Mullen, Matthew G.; Fischer, Natasha Lopes; Yang, Jiekun; Liu, Limin; Trivedi, Prasad; Stelow, Edward B.; Stukenberg, P. Todd; Parsons, J. Thomas; Bauer, Todd W.; Adli, Mazhar.

In: Nature Communications, Vol. 9, No. 1, 4275, 01.12.2018.

Research output: Contribution to journalArticle

Szlachta, K, Kuscu, C, Tufan, T, Adair, SJ, Shang, S, Michaels, AD, Mullen, MG, Fischer, NL, Yang, J, Liu, L, Trivedi, P, Stelow, EB, Stukenberg, PT, Parsons, JT, Bauer, TW & Adli, M 2018, 'CRISPR knockout screening identifies combinatorial drug targets in pancreatic cancer and models cellular drug response', Nature Communications, vol. 9, no. 1, 4275. https://doi.org/10.1038/s41467-018-06676-2
Szlachta, Karol ; Kuscu, Cem ; Tufan, Turan ; Adair, Sara J. ; Shang, Stephen ; Michaels, Alex D. ; Mullen, Matthew G. ; Fischer, Natasha Lopes ; Yang, Jiekun ; Liu, Limin ; Trivedi, Prasad ; Stelow, Edward B. ; Stukenberg, P. Todd ; Parsons, J. Thomas ; Bauer, Todd W. ; Adli, Mazhar. / CRISPR knockout screening identifies combinatorial drug targets in pancreatic cancer and models cellular drug response. In: Nature Communications. 2018 ; Vol. 9, No. 1.
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