CRISPR knockout screening identifies combinatorial drug targets in pancreatic cancer and models cellular drug response
| Autor: | Matthew G. Mullen, Alex D. Michaels, Natasha Lopes Fischer, Mazhar Adli, P. Todd Stukenberg, Sara J. Adair, Karol Szlachta, Todd W. Bauer, Limin Liu, Stephen Shang, Turan Tufan, Edward B. Stelow, Prasad Trivedi, J. Thomas Parsons, Cem Kuscu, Jiekun Yang |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Drug media_common.quotation_subject Science General Physics and Astronomy Mice Nude Antineoplastic Agents Biology Models Biological General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences Gene Knockout Techniques Drug Delivery Systems In vivo Pancreatic cancer Cell Line Tumor medicine CRISPR Animals Combinatorial Chemistry Techniques Humans Clustered Regularly Interspaced Short Palindromic Repeats Genetic Testing lcsh:Science Genetic testing media_common Mitogen-Activated Protein Kinase Kinases Multidisciplinary medicine.diagnostic_test Cell Death Cancer Reproducibility of Results Drug Synergism General Chemistry Cell Cycle Checkpoints medicine.disease 3. Good health Pancreatic Neoplasms 030104 developmental biology Cancer cell Cancer research lcsh:Q |
| Zdroj: | Nature Communications, Vol 9, Iss 1, Pp 1-13 (2018) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | 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. Predicting the response to chemotherapy is a major goal of cancer research. Here the authors use CRISPR knockout screens in pancreatic ductal adenocarcinoma cells to identify deletions synergistic with MEK inhibitors. |
| Databáze: | OpenAIRE |
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