Abstract
To identify physiological targets of drugs and bioactive small molecules, we developed an approach, named DrugTargetSeqR, which combines high-throughput sequencing, computational mutation discovery and clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9-based genome editing. We applied this approach to ispinesib and YM155, drugs that have undergone clinical trials as anticancer agents, and uncovered mechanisms of action and identified genetic and epigenetic mechanisms likely to cause drug resistance in human cancer cells.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology
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Benzamides / pharmacology
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Cell Line, Tumor / drug effects
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Clustered Regularly Interspaced Short Palindromic Repeats*
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Drug Resistance, Neoplasm / drug effects
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Drug Resistance, Neoplasm / genetics*
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Endonucleases / genetics*
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Epigenesis, Genetic
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Genome
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High-Throughput Nucleotide Sequencing / methods*
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Humans
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Imidazoles / pharmacology
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Kinesins / genetics
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Molecular Targeted Therapy
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Mutation
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Naphthoquinones / pharmacology
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Quinazolines / pharmacology
Substances
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Antineoplastic Agents
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Benzamides
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Imidazoles
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Naphthoquinones
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Quinazolines
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ispinesib
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Endonucleases
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Kinesins
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sepantronium