Abstract
Determining mechanisms of drug action in human cells remains a major challenge. Here we describe an approach in which multiple-drug-resistant clones are isolated and transcriptome sequencing is used to find mutations in each clone. Further analysis of mutations common to more than one clone can identify a drug's physiological target and indirect resistance mechanisms, as indicated by our proof-of-concept studies of the cytotoxic anticancer drugs BI 2536 and bortezomib.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Boronic Acids / chemistry
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Boronic Acids / pharmacology
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Bortezomib
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Cell Cycle Proteins / antagonists & inhibitors*
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Cell Cycle Proteins / genetics*
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Cell Line, Tumor
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Drug Resistance, Neoplasm / drug effects
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Drug Resistance, Neoplasm / genetics*
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Humans
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Polo-Like Kinase 1
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / genetics*
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Proto-Oncogene Proteins / antagonists & inhibitors*
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Proto-Oncogene Proteins / genetics*
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Pteridines / chemistry
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Pteridines / pharmacology
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Pyrazines / chemistry
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Pyrazines / pharmacology
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Sequence Analysis, DNA*
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Transcriptome / genetics*
Substances
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Antineoplastic Agents
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BI 2536
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Boronic Acids
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Cell Cycle Proteins
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Proto-Oncogene Proteins
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Pteridines
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Pyrazines
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Bortezomib
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Protein Serine-Threonine Kinases